Advertisement
Review

Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows

Patrick J. Roberts, Vishnu Kumarasamy, Agnieszka K. Witkiewicz and Erik S. Knudsen
DOI: 10.1158/1535-7163.MCT-18-1161 Published August 2020

Abstract

Cyclin-dependent kinases 4 and 6 (CDK4/6) have emerged as important therapeutic targets. Pharmacologic inhibitors of these kinases function to inhibit cell-cycle progression and exert other important effects on the tumor and host environment. Because of their impact on the cell cycle, CDK4/6 inhibitors (CDK4/6i) have been hypothesized to antagonize the antitumor effects of cytotoxic chemotherapy in tumors that are CDK4/6 dependent. However, there are multiple preclinical studies that illustrate potent cooperation between CDK4/6i and chemotherapy. Furthermore, the combination of CDK4/6i and chemotherapy is being tested in clinical trials to both enhance antitumor efficacy and limit toxicity. Exploitation of the noncanonical effects of CDK4/6i could also provide an impetus for future studies in combination with chemotherapy. Thus, while seemingly mutually exclusive mechanisms are at play, the combination of CDK4/6 inhibition and chemotherapy could exemplify rational medicine.

CDK4/6 in Cell-cycle Progression

Cyclin dependent kinases (CDK) are serine/threonine kinases that regulate the sequential progression of the cell cycle in eukaryotic organisms. The molecular functions of these kinases in different phases of the cell cycle have been well characterized (1, 2). The cell-cycle machinery in higher eukaryotes is tightly regulated by the presence of more than 10 proteins in the CDK family that can have overlapping and distinct functions (2). Cell-cycle initiation occurs in G1 phase, which is conventionally governed by the activation of CDK4 and CDK6 kinases that are downstream of mitogenic signals (3–5). The catalytic activity of CDK4 and CDK6 is positively regulated by the binding of D-type cyclins (D1, D2, and D3). Expression of D-type cyclins is induced in response to mitogenic stimuli and remains high as the cells progress to the G1–S phase boundary (6). Therefore, unlike other cyclins and CDKs that are regulated by other components of the cell-cycle machinery, the expression of D-type cyclins, and by extension, CDK4/6-associated kinase activity, largely depend on mitogenic signaling pathways (7, 8). Transcription of D-type cyclins is intimately linked to multiple pathways that coalesce to lead to the accumulation of transcripts (7, 9, 10). Mitogenic signaling pathways also regulate the stability and localization of these proteins (11, 12). Importantly, a host of growth-inhibitory mechanisms also impact CDK4/6 activity, including the induction of endogenous CDK4/6-specific inhibitors with specific stresses (e.g., CDKN2A which encodes p16INK4A), and active mechanisms of cyclin D1 degradation (13, 14). Thus, CDK4/6 activity acts as a sensor linking multiple signaling pathways to the initiation of the cell cycle (15–17).

CDK4/6 regulates the cell cycle through phosphorylation of key substrates. Unlike the prototypical CDK1 and CDK2, which can phosphorylate many substrates, CDK4/6 has a very limited repertoire of targets (18). CDK4 and CDK6 selectively phosphorylate the RB tumor suppressor protein and additional members of the RB family (18–21). RB-family proteins function as transcriptional corepressors and limit the expression of E2F target genes that include multiple genes required for cell-cycle progression, DNA replication, and mitotic progression (22, 23). The phosphorylation of RB, which is initiated by CDK4 or CDK6 serves to limit transcriptional repression and enable progression through latter phases of the cell cycle defining the canonical CDK4/6-RB pathway (Fig. 1A).

Figure 1.
Figure 1.

Different cell cycle states in cancer. A, The Canonical G1/S regulatory circuit: CDK4/6 kinase activity is stimulated downstream of mitogenic/oncogenic signals to initiate the phosphorylation of RB and related proteins. Phosphorylation facilitates the derepression of E2F-family of transcription factors that drive the expression of many genes required for DNA replication, mitosis, and cell division. B, CDK4/6 dependent cells: in cells, tumors, or tissues that are dependent on CDK4/6 activity treatment with pharmacological inhibitors yields the robust activation of RB. This event limits other CDK activities and represses the expression of essential genes for cellular division resulting in a G1–G0–like arrest. C, CDK4/6-independent cells: there are clearly two distinct states that yield CDK4/6 independent proliferation. (1) Loss of RB as occurs in a subset of human tumors removes the down-stream target and as such inhibition of CDK4/6 has minimal efficacy in controlling cell cycle. (2) Through various mechanisms RB phosphorylation can remain during pharmacologic inhibition. This cell-cycle plasticity can be generated through either CDK4/6 or CDK2 complexes and is prevalent in a number of tumor types that retain the RB tumor suppressor.

The requirement for CDK4/6 in cell division has been interrogated utilizing multiple approaches and has illustrated important features of the cell cycle. The inhibition of CDK4/6 by the expression of endogenous inhibitors (e.g., p16INK4A) potently arrests cells that contain a functional RB protein and subsequently limits gene expression controlled by RB/E2F (Fig. 1A). Multiple experimental methods (e.g., antibody injection, RNAi, etc.) have further suggested that D-type cyclins and/or CDK4/6 activity are generally important for progression from G1/S in normal cells as well as multiple cancer models (24). These findings contrast with studies in mouse models that clearly demonstrate that the cell cycle can proceed with genetic deletion of CDK4 and 6 or deletion of all D-type cyclins (25, 26). In this context, adaptation occurs in many tissues by enabling CDK2 or CDK1 activity to drive cell cycle entry. However, genetic suppression of CDK4/6 activity can limit or block tumor development in select models (27–30). This was clearly shown in the context of HER2-driven breast cancer where CDK4/6 activity is required both for tumor etiology and maintenance (31).

Pharmacologic Inhibitors of CDK4/6—Mechanisms of Action and Resistance

Because of the function of CDK4/6 in coordinating cell division, pharmacologic inhibitors have been developed as anticancer drugs. There are five selective CDK4/6 inhibitors (CDK4/6i); palbociclib (PD0332991), ribociclib (LEE011), abemaciclib (LY2835219), trilaciclib (G1T28), and lerociclib (G1T38; refs. 32–38). Currently, three of these drugs are FDA-approved for the treatment of ER+ metastatic breast cancer based on multiple randomized clinical trials (palbociclib, ribociclib, abemaciclib). While all of these compounds are selective for CDK4/6, palbociclib, ribociclib, abemaciclib, and lerociclib are formulated for oral long-term dosing. Trilaciclib was formulated specifically for intravenous delivery and short half-life with the intended goal of preventing chemotherapy-induced host toxicities. Consistent with their mechanism of action, all CDK4/6i have cytostatic activity that is associated with RB-dependent suppression of the G1–S transition (32, 36). Pharmacologic CDK4/6i mimic the effect of RB activation (Fig. 1B) and suppress the expression of genes that are conventionally regulated by the E2F family of transcription factors (39, 40). Because many of these genes are involved in core functions of DNA replication and mitotic progression, and are considered essential for proliferation, the magnitude of transcriptional repression downstream from CDK4/6 inhibition is critical for cytostatic activity.

Multiple determinants of response to CDK4/6 inhibition are being elucidated through both preclinical investigation and the analysis of clinical specimens (Fig. 1C). This work has illustrated that there are multiple cell-cycle–related alterations present in models or tumors (e.g., RB loss or overexpression of cyclin E) that are associated with resistance to CDK4/6 inhibitors (refs. 41–44; Fig. 1C). Conversely, a number of oncogenic signaling pathways (e.g., RAS/MAPK, PTEN/PI3K, or HIPPO) have emerged as contributing to resistance (45–47). These derangements enable escape from CDK4/6 inhibition by facilitating the inactivation/phosphorylation of RB even in the presence of the pharmacologic CDK4/6i. This is believed to occur due to “plasticity,” which is associated with either incomplete inhibition of CDK4/6 or the ability of CDK2 to initiate the phosphorylation of RB. While inhibition of CDK4/6 can arrest cells, dual inhibition of CDK4 and CDK2 has been shown to be required for durable responses in preclinical models (48). In addition, the hyperactivation of CDK2 kinase in breast cancer cells due to overexpression of cyclin E1/cyclin E2 drives resistance to CDK4/6i (49). Conversely, RNAi-mediated knockdown of CCNE1 or CDK2 along with CDK4/6 inhibition can reverse acquired resistance to CDK4/6 inhibition in select models (50–52). Thus, the level of CDK2 activity during response is an important determinant and potential biomarker for the efficacy of CDK4/6i.

The Spectrum of CDK4/6i Tumor Sensitivities and Theoretical Intersection with Chemotherapy

From preclinical and clinical studies, emerging data indicate that there are tumors that are sensitive to CDK4/6i, but that many of these sensitive tumors develop adaptive resistance mechanisms. In these contexts, CDK4/6i combination therapies can enhance the efficacy and durability of the tumor response. In contrast, there are a subset of cancers that are intrinsically CDK4/6-independent (e.g., as a consequence of RB loss; refs. 33, 53). The consequences of the addition of CDK4/6i to chemotherapy must be considered within this framework. In patients with CDK4/6-independent tumors, the anticipated clinical benefit would be to protect normal cells from chemotherapy as the normal cells are sensitive to CDK4/6 inhibition and the tumor cells are insensitive to CDK4/6 inhibition (Fig. 2A). In patients with CDK4/6-dependent tumors, there may be opportunities to enhance antitumor efficacy; however, there is a theoretical risk that CDK4/6 inhibition in this setting may antagonize the intended cytotoxicity of the chemotherapy (Fig. 2B). Preclinical and clinical data suggest that the risk of chemotherapy antagonism by CDK4/6i is not as well understood as initially thought. In addition, the molecular determinants of CDK4/6 independence and dependence are complex, such that it can be difficult to identify those tumors that truly rely upon CDK4/6 for proliferation. We discuss these approaches using the “theoretical” binary tumor classification of CDK4/6-independent and -dependent and acknowledge that the spectrum of dependence may actually be continuous.

Figure 2.
Figure 2.

Differential response to CDK4/6 inhibition determines mode of interaction with chemotherapy. A, CDK4/6 independent tumors: in CDK4/6-independent tumor models, by definition the pharmacologic inhibitors will have minimal effect. SCLC tumors exhibit near universal loss of the RB tumor suppressor, while triple-negative breast cancer exhibits multiple mechanisms that render CDK4/6 independence. In contrast, the host-tissues will be responsive to the CDK4/6 inhibitor and the reduced cell division could be expected to mitigate the toxicity associated with chemotherapy in specific tissue settings. B, Conceptual frame-work for antagonism: chemotherapy represents a diverse class of drugs that exploit the rapid division of tumor cells that impinges on DNA replication or mitotic division. This sensitivity is often enhanced as a result of cell-cycle checkpoint deficits in tumor cells. Ultimately, apoptosis, necrosis, or mitotic catastrophe lead to cytotoxic activity. Because CDK4/6 inhibitors can slow cell-cycle progression they could negatively impact on the efficacy of chemotherapy.

CDK4/6-Independent Tumors—Host Protection

The use of CDK4/6i to arrest cells in the G1 phase in patients with cancer who are being treated with chemotherapy may not seem to be intuitive. However, this biological phenomenon can be exploited to prevent chemotherapy-induced cellular damage of normal cells that harbor an intact RB pathway (refs. 54, 55; Fig. 2A). One of the common side effects of chemotherapy is myelosuppression, that can lead to the exhaustion of hematopoietic stem and progenitor cells (HSPCs; refs. 56–58).

Trilaciclib (G1T28) has been developed to specifically prevent chemotherapy-induced myelosuppression (38). Trilaciclib maintains a selective and reversible G1 arrest in the RB-proficient HPSCs and prevents or mitigates the acute and long-term hematopoietic toxicity of the cytotoxic chemotherapeutic agent, 5-fluorouracil, when administered concurrently (38, 55). Similarly, the cytostatic effect of CDK4/6i can prevent or mitigate the hematopoietic toxicity of ionizing radiation by preventing HSPCs from immediately entering the cell cycle when the cells sense the radiation-induced DNA damage (54).

To translate these findings to the clinic, three randomized, placebo-controlled, double-blind clinical trials designed to evaluate the myelopreservation effects of trilaciclib versus placebo in combination with chemotherapy have been completed in small-cell lung carcinoma (SCLC; refs. 59–62; Table 1). SCLC was chosen as the first clinical setting to test the myelopreservation benefit of trilaciclib because: (i) standard-of-care chemotherapy regimens are myelosuppressive, (ii) SCLC replicates independently of CDK4/6 due to obligate loss of RB (63), thereby minimizing theoretical concerns related to chemotherapy antagonism, and (iii) SCLC treated in the first-line setting is a chemosensitive tumor, which provided an optimal background upon which to demonstrate that trilaciclib does not antagonize chemotherapy efficacy. In all three studies, trilaciclib demonstrated consistent clinical benefit across myelosuppression endpoints, including highly statistically significant improvements for both primary endpoints: the duration of severe neutropenia in cycle 1 (a surrogate for febrile neutropenia and infections) and the percentage of patients with severe neutropenia. Furthermore, integrated analysis from the three studies demonstrated statistically significant improvement across multiple hematopoietic lineages; including neutrophils (duration of severe neutropenia in cycle 1, percentage of patients with severe neutropenia), red blood cells (RBC; percentage of patients with grade 3 or 4 anemia, percentage of patients receiving RBC transfusions on or after 5 weeks, the rate of RBC transfusions on or after 5 weeks), and platelets (percentage of patients with grade 3 or 4 thrombocytopenia; ref. 59). Consistent with the improvement in chemotherapy safety, patient-reported outcome (PRO) measures demonstrated an improved experience for patients receiving trilaciclib, including improved measures of fatigue (59). Importantly, the addition of trilaciclib to chemotherapy did not have an adverse effect on antitumor efficacy (60–62).

View this table:
Table 1.

Clinical studies of CDK4/6 inhibitors with chemotherapy.

Similar to SCLC, triple-negative breast cancer (TNBC) is thought to be a mostly CDK4/6-independent tumor, based on both tumor genetics and the relatively poor response of such tumors to CDK4/6i therapy in preclinical studies (64, 65). Trilaciclib has been tested in combination with gemcitabine and carboplatin in patients with metastatic TNBC (66). In this study, the addition of trilaciclib to chemotherapy generally did not improve myelosuppression endpoints; however, there were positive trends for RBC and platelet measures, and patients in the trilaciclib arms received significantly more chemotherapy than the control. In contrast, the antitumor efficacy results demonstrated a clinically meaningful survival benefit in both combination groups compared with the chemotherapy alone control group. Median progression-free survival was 5.7 months (95% CI: 3.4–9.2) for the control group compared with 9.4 (6.1–13.0; HR: 0.60, P = 0.13) and 7.3 (6.2–12.19; HR: 0.59, P = 0.12) for the two trilaciclib groups. Median overall survival was 12.6 months (6.3–15.6) for the chemotherapy control group compared with 20.1 (10.2–not reached; HR: 0.33, P = 0.028) and 17.8 (12.9–not reached; HR: 0.34, P = 0.0023) for the two trilaciclib + chemotherapy groups. While patients receiving trilaciclib received more chemotherapy, it is unlikely that this can explain the magnitude of survival benefit achieved with transient CDK4/6 inhibition. Instead, an alternative mechanism of action related to enhanced antitumor immunity is more likely as discussed in more detail below.

Antagonism of Chemotherapy-mediated Cytotoxicity in CDK4/6-dependent Preclinical Models

On the basis of the intracellular targets of many chemotherapeutic agents, it is evident that dividing cells are more chemosensitive than arrested cells, which underlies the therapeutic index of such agents (67). Considering the mechanism of action of CDK4/6i in inhibiting cell division through activation of the RB pathway, it is hypothesized that concurrent CDK4/6 inhibition may antagonize the cytotoxic effects of chemotherapeutic agents in tumors that are CDK4/6-dependent (Fig. 2B). Indeed, a number of preclinical reports have described the antagonistic effects of combining a CDK4/6i with chemotherapy (refs. 50, 68–70; Table 2). In breast cancer cell lines, xenografts, and GEMM models, treatment with CDK4/6i can limit the acute induction of tumor-specific toxicity with taxanes, anthracyclines, and platinum-agents (68, 70–72). These effects are RB-dependent and link the antagonism of chemotherapy cytotoxicity with the cell-cycle pause induced by CDK4/6 inhibition (68, 70, 71). In considering these data, it is important to appreciate that most studies utilized conditions where CDK4/6 inhibition elicits profound cell-cycle inhibition and that effects measured on antagonism were relatively short term; however, it should not be discounted that such antagonism could be clinically relevant and caution should be taken to evaluate whether these effects will be seen in specific clinical settings.

View this table:
Table 2.

Preclinical studies demonstrating some evidence of antagonism between CDK4/6 inhibitors and chemotherapy.

Potential Cooperation between CDK4/6i and Chemotherapy in Cancer Therapy in Preclinical Models

In contrast to the above reports, a number of preclinical studies suggest that the combination of chemotherapy and CDK4/6 inhibition can have cooperative antitumor effects; similar observations are beginning to emerge from clinical studies. Palbociclib, ribociclib, and abemaciclib have been shown to enhance, rather than antagonize, chemotherapy cytotoxicity when combined with camptothecin, carboplatin, cisplatin, docetaxel, doxorubicin, 5-FU, gemcitabine, irinotecan, paclitaxel, and temozolomide (36, 73–85). These effects were shown in RB-proficient in vitro and in vivo models of non–small cell lung carcinoma (NSCLC), ovarian cancer, gastric cancer, TNBC, atypical teratoid rhabdoid tumors, Ewing sarcoma, pancreatic cancer, and glioblastoma using both sequential and concurrent dosing schedules (refs. 36, 73–85; Table 3).

View this table:
Table 3.

Preclinical studies demonstrating enhanced efficacy with CDK4/6 inhibitors + chemotherapy treatment.

While the CDK4/6-RB-E2F axis is responsible for controlling expression of genes required for cell-cycle progression, DNA replication, and mitotic progression (23, 39), the unexpected observations of cooperation described above may be due to other less well understood mechanisms. One mechanistic explanation of the enhanced, rather than antagonistic activity of combination CDK4/6i plus chemotherapy regimens, has been the reduced expression of specific E2F-regulated genes, whose products are targeted by chemotherapy (Fig. 3A). Palbociclib treatment reduces thymidylate synthase (TS; 5FU target), Topoisomerase 1, and Topoisomerase 2 alpha expression. These effects on gene expression could potentially enhance the response to select chemotherapies by limiting the threshold needed for efficacy of chemotherapy (70, 77, 86). Similarly, E2F regulates the expression of multiple genes required for DNA damage repair and thus would limit the ability of tumor cells to recover from chemotherapy-mediated damage. Consistent with the impact on DNA repair machinery, it has been shown that CDK4/6i can cooperate with PARP inhibitors ostensibly by limiting the ability of damaged cells to carry out HR-mediated repair (ref. 87; Fig. 3A). Conversely, Gao and colleagues demonstrated a role for MDR (multidrug resistance; P-glycoprotein) in paclitaxel resistance, an effect counteracted by both CDK4 siRNA and palbociclib treatment (76). Finally, multiple studies have demonstrated that CDK4/6 inhibition can enhance chemotherapy-induced apoptosis (76, 79, 85), and that CDK4/6 are upstream regulators of transcription factors that control global gene expression leading to changes in metabolism, DNA repair, and cell plasticity, all of which can render a cancer cell more susceptible to chemotherapy cytotoxicity (88). Collectively, these results suggest that the net effect of concomitant CDK4/6 inhibition during chemotherapy exposure in patients with CDK4/6-dependent tumors will provide cooperation rather than antagonism (Table 3).

Figure 3.
Figure 3.

Cellular response to CDK4/6 inhibition in combination with chemotherapy. A, Downstream from the activation of the RB pathway are the repression of multiple genes involved in different pathways that could impinge on different features of response to distinct chemotherapeutic agents. B, There are multiple mechanisms through which chemotherapy impinges on the activity of CDK2 and CDK4/6 complexes that would be expected to enhance the efficacy of pharmacologic CDK4/6 inhibitors. For example, CDC25A is rapidly degraded or the CDK2-inhibitor P21CIP1 is rapidly induced as a specific response to chemotherapy. Conversely, degradation of cyclin D1 and inhibition of CDK4/6 complexes is a consequence of different chemotherapy agents that induce S-phase block.

Strategies for Incorporating CDK4/6i into Chemotherapy Regimens

On the basis of the available preclinical and clinical data, there are several therapeutic strategies by which CDK4/6i can be incorporated into standard chemotherapy regimens to provide therapeutic benefit to patients:

Protection of normal tissues

As described above, protection of HSPCs to reduce dose-limiting myelosuppression has been demonstrated preclinically and clinically (38, 60–62, 68, 89). While myelosuppression is recognized as a common complication of chemotherapy, damage to other normal tissues including the gastrointestinal track, kidney, and hair follicles also occurs. CDK4/6 inhibition has been shown to ameliorate kidney injury in preclinical models following both cisplatin treatment and acute renal ischemia, and to provide intestinal radioprotection (39, 90, 91). In addition, alopecia, while not life threatening, is one of the most distressing side effects of chemotherapy. Similar to other tissues, transient CDK4/6 inhibition has been shown to protect hair follicles from taxane-induced damage in preclinical models (92). While clinical benefit for this approach has been shown in a CDK4/6-independent setting (SCLC), the question remains whether it can be employed in CDK4/6-dependent tumors without antagonizing chemotherapy antitumor efficacy. In vivo evaluation of trilaciclib with chemotherapy in CDK4/6-sensitive breast cancer models has not shown antagonism at the tumor level, and with some models, the combination shows enhanced antitumor efficacy (93). Interestingly, subset analysis of patients in the trilaciclib metastatic TNBC (mTNBC) study using PAM50 and other molecular stratification approaches revealed no antagonism, and demonstrated improved PFS and OS across all groups (55, 66, 94, 95).

Concurrent interactions, maintenance therapy, and staggered strategies to enhance antitumor efficacy

Because the mechanisms of CDK4/6i and chemotherapy action are distinct, there could be drug interactions that would enhance the efficacy of each class of agent. Chemotherapy is well known to impact CDK biology at multiple points that would be expected to enhance the cytostatic response to CDK4/6 inhibition (73). For example, chemotherapy can impact CDK2 activity via the induction of the endogenous CDK inhibitor p21 or loss of the CDC25a protein phosphatase that would yield increased inhibitory phosphorylation on CDK2 (Fig. 3B). This cooperation has been illustrated in models of pancreatic cancer and other tumor models that do not show robust response to CDK4/6i (96, 97). Regarding resistance to chemotherapy, as discussed above, CDK4/6i can impact the expression of genes associated with DNA repair and dNTP metabolism. These effects could be broadly relevant to chemotherapy that induces DNA damage or is associated with nucleotide metabolism or function (Fig. 3A). Whether these interactions manifest clinically remains unclear, although multiple clinical trials are interrogating CDK4/6i and chemotherapy combinations where there is clear overlap in the treatment.

Given the canonical action of chemotherapy and CDK4/6i, it is appealing to separate/stagger the dosing of the chemotherapy and the CDK4/6i. In this context, the chemotherapy can have the desired impact of killing the tumor cells, while the CDK4/6i prevents the expansion of cells that are not killed by the chemotherapy (98). In ovarian cancer models, following the release from cisplatin-mediated S-phase arrest, tumor cells undergo normal cell-cycle progression and proliferation, which is significantly blocked by CDK4/6 inhibition, indicating a positive interaction (80). Similarly, the targeted microtubule poison trastuzumab-emtansine (T-DM1) displayed a cooperative antitumor effect where CDK4/6i could block the recovery of residual cells following T-DM1 treatment (99). Presently, there are a number of clinical trials that explore the interaction of CDK4/6 inhibition and chemotherapy using dosing strategies to enhance durability of response (Table 1). In one of the first reported trials, the combination of paclitaxel with palbociclib appeared to have efficacy in heavily pretreated breast cancer (100).

As CDK4/6i are not associated with cumulative toxicity, which is a common feature of chemotherapy, they can be given for long periods of time. Therefore, chronic administration of a CDK4/6i in the maintenance treatment setting, after the tumor has been debulked and chemotherapy discontinued could lead to improved patient outcomes by delaying tumor progression and or allowing the host immune system to eliminate the residual disease (80).

Enhancing the response to immunotherapy

There is significant preclinical data demonstrating that CDK4/6i can enhance immune checkpoint inhibitor (ICI) efficacy through enhanced T-cell activation, increased antigen presentation, increased expression of PD-L1, and reduced T-cell exclusion and immune evasion gene signature (88, 101, 102) In the clinic, chemotherapy has successfully been used to enhance ICI efficacy (103–108) through induction of immunogenic cell death, enhancement of immunosurveillance, and T-cell activity, and reduction of immunosuppressive cell types (109–112). Despite these benefits, chemotherapy-induced myelosuppression and immunosuppression may limit the full benefit of combinatorial treatments with ICIs. Given that intratumor immune cells are highly proliferative, one strategy to further enhance chemotherapy/ICI combinations is through transient CDK4/6 inhibition during chemotherapy exposure. Trilaciclib has been shown to favorably alter the tumor immune microenvironment through transient T-cell inhibition (113, 114). Treatment of immunocompetent tumor models with trilaciclib plus chemotherapy/ICI combinations significantly improved antitumor efficacy and survival compared with chemotherapy/ICI combinations (113, 114).

Summary and Underexplored Areas

In summary, while it was originally hypothesized that CDK4/6i combined with chemotherapy could potentially result in antagonistic antitumor effects (at least in CDK4/6-dependent tumors), emerging data suggest that these agents can be safely combined using different clinical strategies to enhance antitumor efficacy and/or reduce chemotherapy-induced toxicity. There are a number of unanswered questions whose answers could help guide implementation of these strategies in the clinic. Understanding which of these clinical strategies would be best employed in tumors that are “truly” CDK4/6-dependent is still needed. However, identifying “truly” CDK4/6-dependent tumors remains elusive as predictive biomarkers have not been validated in clinical practice. Identification and validation of such biomarkers would allow clinical testing of CDK4/6i + chemotherapy combinations in a homogeneous CDK4/6-dependent tumor population to definitively determine whether CDK4/6 inhibition during chemotherapy exposure interferes with the intended antitumor efficacy of chemotherapy. In addition, understanding the contribution of antitumor effects arising from cell-cycle inhibition in tumor cells versus nontumor cells (e.g., cancer associated fibroblasts and immune cells) and through noncanonical biological processes controlled by CDK4/6 will further aid the rational design of novel CDK4/6i plus chemotherapy and/or immunotherapy regimens.

Disclosure of Potential Conflicts of Interest

P.J. Roberts is a senior director of translational medicine at G1 Therapeutics and has ownership interest (including patents) in G1 Therapeutics. No potential conflicts of interest were disclosed by the other authors.

Acknowledgments

The authors acknowledge their colleagues at Roswell Park and G1 Therapeutics for thoughtful discussion and review of the manuscript. This work was supported by grants AKW and ESK from the NIH CA211878 and CA247362.

Footnotes

  • Mol Cancer Ther 2020;19:1575–88

  • Received February 26, 2020.
  • Revision received April 17, 2020.
  • Accepted June 10, 2020.
  • Published first June 16, 2020.

References

  1. 1.↵
    1. Beach D,
    2. Durkacz B,
    3. Nurse P
    . Functionally homologous cell cycle control genes in budding and fission yeast. Nature 1982;300:706–9.
    OpenUrlCrossRefPubMed
  2. 2.↵
    1. Nurse P,
    2. Thuriaux P
    . Regulatory genes controlling mitosis in the fission yeast Schizosaccharomyces pombe. Genetics 1980;96:627–37.
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. Baker SJ,
    2. Reddy EP
    . CDK4: a key player in the cell cycle, development, and cancer. Genes Cancer 2012;3:658–69.
    OpenUrlCrossRefPubMed
  4. 4.↵
    1. Duronio RJ,
    2. Xiong Y
    . Signaling pathways that control cell proliferation. Cold Spring Harb Perspect Biol 2013;5:a008904.
    OpenUrlAbstract/FREE Full Text
  5. 5.↵
    1. Morrison DK
    . MAP kinase pathways. Cold Spring Harb Perspect Biol 2012;4:a011254.
    OpenUrlCrossRefPubMed
  6. 6.↵
    1. Pagano M,
    2. Theodoras AM,
    3. Tam SW,
    4. Draetta GF
    . Cyclin D1-mediated inhibition of repair and replicative DNA synthesis in human fibroblasts. Genes Dev 1994;8:1627–39.
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Albanese C,
    2. Johnson J,
    3. Watanabe G,
    4. Eklund N,
    5. Vu D,
    6. Arnold A,
    7. et al.
    Transforming p21ras mutants and c-Ets-2 activate the cyclin D1 promoter through distinguishable regions. J Biol Chem 1995;270:23589–97.
    OpenUrlAbstract/FREE Full Text
  8. 8.↵
    1. Sherr CJ
    . D-type cyclins. Trends Biochem Sci 1995;20:187–90.
    OpenUrlCrossRefPubMed
  9. 9.↵
    1. Matsushime H,
    2. Roussel MF,
    3. Ashmun RA,
    4. Sherr CJ
    . Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle. Cell 1991;65:701–13.
    OpenUrlCrossRefPubMed
  10. 10.↵
    1. Brown JR,
    2. Nigh E,
    3. Lee RJ,
    4. Ye H,
    5. Thompson MA,
    6. Saudou F,
    7. et al.
    Fos family members induce cell cycle entry by activating cyclin D1. Mol Cell Biol 1998;18:5609–19.
    OpenUrlAbstract/FREE Full Text
  11. 11.↵
    1. Diehl JA
    . Cycling to cancer with cyclin D1. Cancer Biol Ther 2002;1:226–31.
    OpenUrlCrossRefPubMed
  12. 12.↵
    1. Diehl JA,
    2. Zindy F,
    3. Sherr CJ
    . Inhibition of cyclin D1 phosphorylation on threonine-286 prevents its rapid degradation via the ubiquitin-proteasome pathway. Genes Dev 1997;11:957–72.
    OpenUrlAbstract/FREE Full Text
  13. 13.↵
    1. Agami R,
    2. Bernards R
    . Distinct initiation and maintenance mechanisms cooperate to induce G1 cell cycle arrest in response to DNA damage. Cell 2000;102:55–66.
    OpenUrlCrossRefPubMed
  14. 14.↵
    1. Serrano M,
    2. Hannon GJ,
    3. Beach D
    . A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366:704–7.
    OpenUrlCrossRefPubMed
  15. 15.↵
    1. Shtutman M,
    2. Zhurinsky J,
    3. Simcha I,
    4. Albanese C,
    5. D'Amico M,
    6. Pestell R,
    7. et al.
    The cyclin D1 gene is a target of the beta-catenin/LEF-1 pathway. Proc Natl Acad Sci U S A 1999;96:5522–7.
    OpenUrlAbstract/FREE Full Text
  16. 16.↵
    1. Joyce D,
    2. Bouzahzah B,
    3. Fu M,
    4. Albanese C,
    5. D'Amico M,
    6. Steer J,
    7. et al.
    Integration of Rac-dependent regulation of cyclin D1 transcription through a nuclear factor-kappaB-dependent pathway. J Biol Chem 1999;274:25245–9.
    OpenUrlAbstract/FREE Full Text
  17. 17.↵
    1. Alt JR,
    2. Cleveland JL,
    3. Hannink M,
    4. Diehl JA
    . Phosphorylation-dependent regulation of cyclin D1 nuclear export and cyclin D1-dependent cellular transformation. Genes Dev 2000;14:3102–14.
    OpenUrlAbstract/FREE Full Text
  18. 18.↵
    1. Matsushime H,
    2. Ewen ME,
    3. Strom DK,
    4. Kato JY,
    5. Hanks SK,
    6. Roussel MF,
    7. et al.
    Identification and properties of an atypical catalytic subunit (p34PSK-J3/cdk4) for mammalian D type G1 cyclins. Cell 1992;71:323–34.
    OpenUrlCrossRefPubMed
  19. 19.↵
    1. Kato J,
    2. Matsushime H,
    3. Hiebert SW,
    4. Ewen ME,
    5. Sherr CJ
    . Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev 1993;7:331–42.
    OpenUrlFREE Full Text
  20. 20.↵
    1. Meyerson M,
    2. Harlow E
    . Identification of G1 kinase activity for cdk6, a novel cyclin D partner. Mol Cell Biol 1994;14:2077–86.
    OpenUrlAbstract/FREE Full Text
  21. 21.↵
    1. Farkas T,
    2. Hansen K,
    3. Holm K,
    4. Lukas J,
    5. Bartek J
    . Distinct phosphorylation events regulate p130- and p107-mediated repression of E2F-4. J Biol Chem 2002;277:26741–52.
    OpenUrlAbstract/FREE Full Text
  22. 22.↵
    1. Ren B,
    2. Cam H,
    3. Takahashi Y,
    4. Volkert T,
    5. Terragni J,
    6. Young RA,
    7. et al.
    E2F integrates cell cycle progression with DNA repair, replication, and G(2)/M checkpoints. Genes Dev 2002;16:245–56.
    OpenUrlAbstract/FREE Full Text
  23. 23.↵
    1. Burkhart DL,
    2. Sage J
    . Cellular mechanisms of tumour suppression by the retinoblastoma gene. Nat Rev Cancer 2008;8:671–82.
    OpenUrlCrossRefPubMed
  24. 24.↵
    1. Knudsen ES,
    2. Witkiewicz AK
    . The strange case of CDK4/6 inhibitors: mechanisms, resistance, and combination strategies. Trends Cancer 2017;3:39–55.
    OpenUrlCrossRefPubMed
  25. 25.↵
    1. Malumbres M,
    2. Sotillo R,
    3. Santamaria D,
    4. Galan J,
    5. Cerezo A,
    6. Ortega S,
    7. et al.
    Mammalian cells cycle without the D-type cyclin-dependent kinases Cdk4 and Cdk6. Cell 2004;118:493–504.
    OpenUrlCrossRefPubMed
  26. 26.↵
    1. Kozar K,
    2. Ciemerych MA,
    3. Rebel VI,
    4. Shigematsu H,
    5. Zagozdzon A,
    6. Sicinska E,
    7. et al.
    Mouse development and cell proliferation in the absence of D-cyclins. Cell 2004;118:477–91.
    OpenUrlCrossRefPubMed
  27. 27.↵
    1. Santamaria D,
    2. Barriere C,
    3. Cerqueira A,
    4. Hunt S,
    5. Tardy C,
    6. Newton K,
    7. et al.
    Cdk1 is sufficient to drive the mammalian cell cycle. Nature 2007;448:811–5.
    OpenUrlCrossRefPubMed
  28. 28.↵
    1. Malumbres M,
    2. Barbacid M
    . Is cyclin D1-CDK4 kinase a bona fide cancer target? Cancer Cell 2006;9:2–4.
    OpenUrlCrossRefPubMed
  29. 29.↵
    1. Yu Q,
    2. Geng Y,
    3. Sicinski P
    . Specific protection against breast cancers by cyclin D1 ablation. Nature 2001;411:1017–21.
    OpenUrlCrossRefPubMed
  30. 30.↵
    1. Landis MW,
    2. Pawlyk BS,
    3. Li T,
    4. Sicinski P,
    5. Hinds PW
    . Cyclin D1-dependent kinase activity in murine development and mammary tumorigenesis. Cancer Cell 2006;9:13–22.
    OpenUrlCrossRefPubMed
  31. 31.↵
    1. Yu Q,
    2. Sicinska E,
    3. Geng Y,
    4. Ahnstrom M,
    5. Zagozdzon A,
    6. Kong Y,
    7. et al.
    Requirement for CDK4 kinase function in breast cancer. Cancer Cell 2006;9:23–32.
    OpenUrlCrossRefPubMed
  32. 32.↵
    1. Fry DW,
    2. Harvey PJ,
    3. Keller PR,
    4. Elliott WL,
    5. Meade M,
    6. Trachet E,
    7. et al.
    Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol Cancer Ther 2004;3:1427–38.
    OpenUrlAbstract/FREE Full Text
  33. 33.↵
    1. Finn RS,
    2. Dering J,
    3. Conklin D,
    4. Kalous O,
    5. Cohen DJ,
    6. Desai AJ,
    7. et al.
    PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res 2009;11:R77.
    OpenUrlCrossRefPubMed
  34. 34.↵
    1. Tripathy D,
    2. Bardia A,
    3. Sellers WR
    . Ribociclib (LEE011): mechanism of action and clinical impact of this selective cyclin-dependent kinase 4/6 inhibitor in various solid tumors. Clin Cancer Res 2017;23:3251–62.
    OpenUrlAbstract/FREE Full Text
  35. 35.↵
    1. Corona SP,
    2. Generali D
    . Abemaciclib: a CDK4/6 inhibitor for the treatment of HR+/HER2− advanced breast cancer. Drug Des Devel Ther 2018;12:321–30.
    OpenUrl
  36. 36.↵
    1. Gelbert LM,
    2. Cai S,
    3. Lin X,
    4. Sanchez-Martinez C,
    5. Del Prado M,
    6. Lallena MJ,
    7. et al.
    Preclinical characterization of the CDK4/6 inhibitor LY2835219: in-vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine. Invest New Drugs 2014;32:825–37.
    OpenUrlCrossRefPubMed
  37. 37.↵
    1. Bisi JE,
    2. Sorrentino JA,
    3. Jordan JL,
    4. Darr DD,
    5. Roberts PJ,
    6. Tavares FX,
    7. et al.
    Preclinical development of G1T38: a novel, potent and selective inhibitor of cyclin dependent kinases 4/6 for use as an oral antineoplastic in patients with CDK4/6 sensitive tumors. Oncotarget 2017;8:42343–58.
    OpenUrl
  38. 38.↵
    1. Bisi JE,
    2. Sorrentino JA,
    3. Roberts PJ,
    4. Tavares FX,
    5. Strum JC
    . Preclinical characterization of G1T28: a novel CDK4/6 inhibitor for reduction of chemotherapy-induced myelosuppression. Mol Cancer Ther 2016;15:783–93.
    OpenUrlAbstract/FREE Full Text
  39. 39.↵
    1. DiRocco DP,
    2. Bisi J,
    3. Roberts P,
    4. Strum J,
    5. Wong KK,
    6. Sharpless N,
    7. et al.
    CDK4/6 inhibition induces epithelial cell cycle arrest and ameliorates acute kidney injury. Am J Physiol Renal Physiol 2014;306:F379–88.
    OpenUrlCrossRefPubMed
  40. 40.↵
    1. Knudsen ES,
    2. Witkiewicz AK
    . Defining the transcriptional and biological response to CDK4/6 inhibition in relation to ER+/HER2− breast cancer. Oncotarget 2016;7:69111–23.
    OpenUrlCrossRef
  41. 41.↵
    1. Dean JL,
    2. Thangavel C,
    3. McClendon AK,
    4. Reed CA,
    5. Knudsen ES
    . Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 2010;29:4018–32.
    OpenUrlCrossRefPubMed
  42. 42.↵
    1. Konecny GE,
    2. Winterhoff B,
    3. Kolarova T,
    4. Qi J,
    5. Manivong K,
    6. Dering J,
    7. et al.
    Expression of p16 and retinoblastoma determines response to CDK4/6 inhibition in ovarian cancer. Clin Cancer Res 2011;17:1591–602.
    OpenUrlAbstract/FREE Full Text
  43. 43.↵
    1. Wiedemeyer WR,
    2. Dunn IF,
    3. Quayle SN,
    4. Zhang J,
    5. Chheda MG,
    6. Dunn GP,
    7. et al.
    Pattern of retinoblastoma pathway inactivation dictates response to CDK4/6 inhibition in GBM. Proc Natl Acad Sci U S A 2010;107:11501–6.
    OpenUrlAbstract/FREE Full Text
  44. 44.↵
    1. Marzec M,
    2. Kasprzycka M,
    3. Lai R,
    4. Gladden AB,
    5. Wlodarski P,
    6. Tomczak E,
    7. et al.
    Mantle cell lymphoma cells express predominantly cyclin D1a isoform and are highly sensitive to selective inhibition of CDK4 kinase activity. Blood 2006;108:1744–50.
    OpenUrlAbstract/FREE Full Text
  45. 45.↵
    1. de Leeuw R,
    2. McNair C,
    3. Schiewer MJ,
    4. Neupane NP,
    5. Brand LJ,
    6. Augello MA,
    7. et al.
    MAPK reliance via acquired CDK4/6 inhibitor resistance in cancer. Clin Cancer Res 2018;24:4201–14.
    OpenUrlAbstract/FREE Full Text
  46. 46.↵
    1. Cornell L,
    2. Wander SA,
    3. Visal T,
    4. Wagle N,
    5. Shapiro GI
    . MicroRNA-mediated suppression of the TGF-beta pathway confers transmissible and reversible CDK4/6 inhibitor resistance. Cell Rep 2019;26:2667–80.
    OpenUrl
  47. 47.↵
    1. Formisano L,
    2. Lu Y,
    3. Servetto A,
    4. Hanker AB,
    5. Jansen VM,
    6. Bauer JA,
    7. et al.
    Aberrant FGFR signaling mediates resistance to CDK4/6 inhibitors in ER+ breast cancer. Nat Commun 2019;10:1373.
    OpenUrl
  48. 48.↵
    1. Patel P,
    2. Tsiperson V,
    3. Gottesman SRS,
    4. Somma J,
    5. Blain SW
    . Dual inhibition of CDK4 and CDK2 via targeting p27 tyrosine phosphorylation induces a potent and durable response in breast cancer cells. Mol Cancer Res 2018;16:361–77.
    OpenUrlAbstract/FREE Full Text
  49. 49.↵
    1. Portman N,
    2. Alexandrou S,
    3. Carson E,
    4. Wang S,
    5. Lim E,
    6. Caldon CE
    . Overcoming CDK4/6 inhibitor resistance in ER-positive breast cancer. Endocr Relat Cancer 2019;26:R15–R30.
    OpenUrl
  50. 50.↵
    1. Franco J,
    2. Witkiewicz AK,
    3. Knudsen ES
    . CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer. Oncotarget 2014;5:6512–25.
    OpenUrlCrossRefPubMed
  51. 51.↵
    1. Knudsen ES,
    2. Kumarasamy V,
    3. Ruiz A,
    4. Sivinski J,
    5. Chung S,
    6. Grant A,
    7. et al.
    Cell cycle plasticity driven by MTOR signaling: integral resistance to CDK4/6 inhibition in patient-derived models of pancreatic cancer. Oncogene 2019;38:3355–70.
    OpenUrlCrossRefPubMed
  52. 52.↵
    1. Herrera-Abreu MT,
    2. Palafox M,
    3. Asghar U,
    4. Rivas MA,
    5. Cutts RJ,
    6. Garcia-Murillas I,
    7. et al.
    Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer. Cancer Res 2016;76:2301–13.
    OpenUrlAbstract/FREE Full Text
  53. 53.↵
    1. Bertucci F,
    2. Ng CKY,
    3. Patsouris A,
    4. Droin N,
    5. Piscuoglio S,
    6. Carbuccia N,
    7. et al.
    Genomic characterization of metastatic breast cancers. Nature 2019;569:560–4.
    OpenUrlCrossRefPubMed
  54. 54.↵
    1. Johnson SM,
    2. Torrice CD,
    3. Bell JF,
    4. Monahan KB,
    5. Jiang Q,
    6. Wang Y,
    7. et al.
    Mitigation of hematologic radiation toxicity in mice through pharmacological quiescence induced by CDK4/6 inhibition. J Clin Invest 2010;120:2528–36.
    OpenUrlCrossRefPubMed
  55. 55.↵
    1. Asghar US,
    2. Barr AR,
    3. Cutts R,
    4. Beaney M,
    5. Babina I,
    6. Sampath D,
    7. et al.
    Single-cell dynamics determines response to CDK4/6 inhibition in triple-negative breast cancer. Clin Cancer Res 2017;23:5561–72.
    OpenUrlAbstract/FREE Full Text
  56. 56.↵
    1. Gardner RV,
    2. Lerner C,
    3. Astle CM,
    4. Harrison DE
    . Assessing permanent damage to primitive hematopoietic stem cells after chemotherapy using the competitive repopulation assay. Cancer Chemother Pharmacol 1993;32:450–4.
    OpenUrlCrossRefPubMed
  57. 57.↵
    1. Gardner RV
    . Long term hematopoietic damage after chemotherapy and cytokine. Front Biosci 1999;4:e47–57.
    OpenUrlCrossRefPubMed
  58. 58.↵
    1. Mauch P,
    2. Constine L,
    3. Greenberger J,
    4. Knospe W,
    5. Sullivan J,
    6. Liesveld JL,
    7. et al.
    Hematopoietic stem cell compartment: acute and late effects of radiation therapy and chemotherapy. Int J Radiat Oncol Biol Phys 1995;31:1319–39.
    OpenUrlCrossRefPubMed
  59. 59.↵
    1. Weiss J SK,
    2. Gwaltney C,
    3. Daniel D,
    4. Adler S,
    5. Wo0lfe S,
    6. Malik RK,
    7. et al.
    Positive effects of trilaciclib on patient myelosuppression-related symptoms and fucntioning: results from three phase 2 randomized, double-blind, placebo-controlled small cell lung cancer trials. Support Care Cancer 2019;27:S274.
    OpenUrl
  60. 60.↵
    1. Weiss JM,
    2. Csoszi T,
    3. Maglakelidze M,
    4. Hoyer RJ,
    5. Beck JT,
    6. Domine Gomez M,
    7. et al.
    Myelopreservation with the CDK4/6 inhibitor trilaciclib in patients with small-cell lung cancer receiving first-line chemotherapy: a phase Ib/randomized phase II trial. Ann Oncol 2019;30:1613–21.
    OpenUrl
  61. 61.↵
    1. Hart LL,
    2. Andric ZG,
    3. Hussein MA,
    4. Ferrarotto R,
    5. Beck JT,
    6. Subramanian J,
    7. et al.
    Effect of trilaciclib, a CDK 4/6 inhibitor, on myelosuppression in patients with previously treated extensive-stage small cell lung cancer receiving topotecan. J Clin Oncol 2019;37:8505.
    OpenUrl
  62. 62.↵
    1. Daniel D,
    2. Kuchava V,
    3. Bondarenko I,
    4. Ivashchuk O,
    5. Spigel D,
    6. Dasgupta A,
    7. et al.
    1742PDTrilaciclib (T) decreases myelosuppression in extensive-stage small cell lung cancer (ES-SCLC) patients receiving first-line chemotherapy plus atezolizumab. Ann Oncol 2019;30(5 suppl):v713.
    OpenUrl
  63. 63.↵
    1. George J,
    2. Lim JS,
    3. Jang SJ,
    4. Cun Y,
    5. Ozretic L,
    6. Kong G,
    7. et al.
    Comprehensive genomic profiles of small cell lung cancer. Nature 2015;524:47–53.
    OpenUrlCrossRefPubMed
  64. 64.↵
    1. Patnaik A,
    2. Rosen LS,
    3. Tolaney SM,
    4. Tolcher AW,
    5. Goldman JW,
    6. Gandhi L,
    7. et al.
    Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors. Cancer Discov 2016;6:740–53.
    OpenUrlAbstract/FREE Full Text
  65. 65.↵
    1. Witkiewicz AK,
    2. Knudsen ES.
    Retinoblastoma tumor suppressor pathway in breast cancer: prognosis, precision medicine, and therapeutic interventions. Breast Cancer Res 2014;16:207.
    OpenUrlCrossRefPubMed
  66. 66.↵
    1. Tan AR,
    2. Wright GS,
    3. Thummala AR,
    4. Danso MA,
    5. Popovic L,
    6. Pluard TJ,
    7. et al.
    Trilaciclib plus chemotherapy versus chemotherapy alone in patients with metastatic triple-negative breast cancer: a multicentre, randomised, open-label, phase 2 trial. Lancet Oncol 2019;20:1587–601.
    OpenUrl
  67. 67.↵
    1. Gudkov AV,
    2. Komarova EA
    . Radioprotection: smart games with death. J Clin Invest 2010;120:2270–3.
    OpenUrlCrossRefPubMed
  68. 68.↵
    1. Roberts PJ,
    2. Bisi JE,
    3. Strum JC,
    4. Combest AJ,
    5. Darr DB,
    6. Usary JE,
    7. et al.
    Multiple roles of cyclin-dependent kinase 4/6 inhibitors in cancer therapy. J Natl Cancer Inst 2012;104:476–87.
    OpenUrlCrossRefPubMed
  69. 69.↵
    1. McClendon AK,
    2. Dean JL,
    3. Rivadeneira DB,
    4. Yu JE,
    5. Reed CA,
    6. Gao E,
    7. et al.
    CDK4/6 inhibition antagonizes the cytotoxic response to anthracycline therapy. Cell Cycle 2012;11:2747–55.
    OpenUrlCrossRefPubMed
  70. 70.↵
    1. Dean JL,
    2. McClendon AK,
    3. Knudsen ES
    . Modification of the DNA damage response by therapeutic CDK4/6 inhibition. J Biol Chem 2012;287:29075–87.
    OpenUrlAbstract/FREE Full Text
  71. 71.↵
    1. Witkiewicz AK,
    2. Chung S,
    3. Brough R,
    4. Vail P,
    5. Franco J,
    6. Lord CJ,
    7. et al.
    Targeting the vulnerability of RB tumor suppressor loss in triple-negative breast cancer. Cell Rep 2018;22:1185–99.
    OpenUrl
  72. 72.↵
    1. Jin D,
    2. Tran N,
    3. Thomas N,
    4. Tran DD
    . Combining CDK4/6 inhibitors ribociclib and palbociclib with cytotoxic agents does not enhance cytotoxicity. PLoS One 2019;14:e0223555.
    OpenUrl
  73. 73.↵
    1. Cao J,
    2. Zhu Z,
    3. Wang H,
    4. Nichols TC,
    5. Lui GYL,
    6. Deng S,
    7. et al.
    Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer. Oncogene 2019;38:4125–41.
    OpenUrl
  74. 74.↵
    1. Chou A,
    2. Froio D,
    3. Nagrial AM,
    4. Parkin A,
    5. Murphy KJ,
    6. Chin VT,
    7. et al.
    Tailored first-line and second-line CDK4-targeting treatment combinations in mouse models of pancreatic cancer. Gut 2018;67:2142–55.
    OpenUrlAbstract/FREE Full Text
  75. 75.↵
    1. Dowless M,
    2. Lowery CD,
    3. Shackleford T,
    4. Renschler M,
    5. Stephens J,
    6. Flack R,
    7. et al.
    Abemaciclib is active in preclinical models of ewing sarcoma via multipronged regulation of cell cycle, DNA methylation, and interferon pathway signaling. Clin Cancer Res 2018;24:6028–39.
    OpenUrlAbstract/FREE Full Text
  76. 76.↵
    1. Gao Y,
    2. Shen J,
    3. Choy E,
    4. Mankin H,
    5. Hornicek F,
    6. Duan Z
    . Inhibition of CDK4 sensitizes multidrug resistant ovarian cancer cells to paclitaxel by increasing apoptosiss. Cell Oncol 2017;40:209–18.
    OpenUrl
  77. 77.↵
    1. Hamilton G,
    2. Klameth L,
    3. Rath B,
    4. Thalhammer T
    . Synergism of cyclin-dependent kinase inhibitors with camptothecin derivatives in small cell lung cancer cell lines. Molecules 2014;19:2077–88.
    OpenUrl
  78. 78.↵
    1. Hashizume R,
    2. Zhang A,
    3. Mueller S,
    4. Prados MD,
    5. Lulla RR,
    6. Goldman S,
    7. et al.
    Inhibition of DNA damage repair by the CDK4/6 inhibitor palbociclib delays irradiated intracranial atypical teratoid rhabdoid tumor and glioblastoma xenograft regrowth. Neuro Oncol 2016;18:1519–28.
    OpenUrlCrossRefPubMed
  79. 79.↵
    1. Huang X,
    2. Di Liberto M,
    3. Jayabalan D,
    4. Liang J,
    5. Ely S,
    6. Bretz J,
    7. et al.
    Prolonged early G(1) arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. Blood 2012;120:1095–106.
    OpenUrlAbstract/FREE Full Text
  80. 80.↵
    1. Iyengar M,
    2. O'Hayer P,
    3. Cole A,
    4. Sebastian T,
    5. Yang K,
    6. Coffman L,
    7. et al.
    CDK4/6 inhibition as maintenance and combination therapy for high grade serous ovarian cancer. Oncotarget 2018;9:15658–72.
    OpenUrlCrossRef
  81. 81.↵
    1. O'Brien N,
    2. Conklin D,
    3. Beckmann R,
    4. Luo T,
    5. Chau K,
    6. Thomas J,
    7. et al.
    Preclinical activity of abemaciclib alone or in combination with antimitotic and targeted therapies in breast cancer. Mol Cancer Ther 2018;17:897–907.
    OpenUrlAbstract/FREE Full Text
  82. 82.↵
    1. Raub TJ,
    2. Wishart GN,
    3. Kulanthaivel P,
    4. Staton BA,
    5. Ajamie RT,
    6. Sawada GA,
    7. et al.
    Brain exposure of two selective dual CDK4 and CDK6 inhibitors and the antitumor activity of CDK4 and CDK6 inhibition in combination with temozolomide in an intracranial glioblastoma xenograft. Drug Metab Dispos 2015;43:1360–71.
    OpenUrlAbstract/FREE Full Text
  83. 83.↵
    1. Wang D,
    2. Sun Y,
    3. Li W,
    4. Ye F,
    5. Zhang Y,
    6. Guo Y,
    7. et al.
    Antiproliferative effects of the CDK6 inhibitor PD0332991 and its effect on signaling networks in gastric cancer cells. Int J Mol Med 2018;41:2473–84.
    OpenUrl
  84. 84.↵
    1. Zhang J,
    2. Zhou L,
    3. Zhao S,
    4. Dicker DT,
    5. El-Deiry WS
    . The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia. Cell Cycle 2017;16:1193–200.
    OpenUrl
  85. 85.↵
    1. Zhang XH,
    2. Cheng Y,
    3. Shin JY,
    4. Kim JO,
    5. Oh JE,
    6. Kang JH
    . A CDK4/6 inhibitor enhances cytotoxicity of paclitaxel in lung adenocarcinoma cells harboring mutant KRAS as well as wild-type KRAS. Cancer Biol Ther 2013;14:597–605.
    OpenUrlCrossRefPubMed
  86. 86.↵
    1. Min A,
    2. Kim JE,
    3. Kim YJ,
    4. Lim JM,
    5. Kim S,
    6. Kim JW,
    7. et al.
    Cyclin E overexpression confers resistance to the CDK4/6 specific inhibitor palbociclib in gastric cancer cells. Cancer Lett 2018;430:123–32.
    OpenUrl
  87. 87.↵
    1. Yi J,
    2. Liu C,
    3. Tao Z,
    4. Wang M,
    5. Jia Y,
    6. Sang X,
    7. et al.
    MYC status as a determinant of synergistic response to Olaparib and Palbociclib in ovarian cancer. EBioMedicine 2019;43:225–37.
    OpenUrl
  88. 88.↵
    1. Klein ME,
    2. Kovatcheva M,
    3. Davis LE,
    4. Tap WD,
    5. Koff A
    . CDK4/6 inhibitors: the mechanism of action may not be as simple as once thought. Cancer Cell 2018;34:9–20.
    OpenUrlCrossRef
  89. 89.↵
    1. He S,
    2. Roberts PJ,
    3. Sorrentino JA,
    4. Bisi JE,
    5. Storrie-White H,
    6. Tiessen RG,
    7. et al.
    Transient CDK4/6 inhibition protects hematopoietic stem cells from chemotherapy-induced exhaustion. Sci Transl Med 2017;9:eaal3986.
    OpenUrlAbstract/FREE Full Text
  90. 90.↵
    1. Pabla N,
    2. Gibson AA,
    3. Buege M,
    4. Ong SS,
    5. Li L,
    6. Hu S,
    7. et al.
    Mitigation of acute kidney injury by cell-cycle inhibitors that suppress both CDK4/6 and OCT2 functions. Proc Natl Acad Sci U S A 2015;112:5231–6.
    OpenUrlAbstract/FREE Full Text
  91. 91.↵
    1. Wei L,
    2. Leibowitz BJ,
    3. Wang X,
    4. Epperly M,
    5. Greenberger J,
    6. Zhang L,
    7. et al.
    Inhibition of CDK4/6 protects against radiation-induced intestinal injury in mice. J Clin Invest 2016;126:4076–87.
    OpenUrlCrossRef
  92. 92.↵
    1. Purba TS,
    2. Ng'andu K,
    3. Brunken L,
    4. Smart E,
    5. Mitchell E,
    6. Hassan N,
    7. et al.
    CDK4/6 inhibition mitigates stem cell damage in a novel model for taxane-induced alopecia. EMBO Mol Med 2019;11:e11031.
    OpenUrl
  93. 93.↵
    1. Sorrentino JA BJ,
    2. Thompson D,
    3. Lai AY,
    4. Hall CR,
    5. Strum JC,
    6. Roberts PJ
    . Trilaciclib, a Cdk4/6 inhibitor, does not impair the efficacy of chemotherapy in Cdk4/6-dependent tumor models. Eur J Cancer 2018;103:e23–e147.
    OpenUrl
  94. 94.↵
    1. Lehmann BD,
    2. Jovanovic B,
    3. Chen X,
    4. Estrada MV,
    5. Johnson KN,
    6. Shyr Y,
    7. et al.
    Refinement of triple-negative breast cancer molecular subtypes: implications for neoadjuvant chemotherapy selection. PLoS One 2016;11:e0157368.
    OpenUrlCrossRef
  95. 95.↵
    1. Prat A,
    2. Bianchini G,
    3. Thomas M,
    4. Belousov A,
    5. Cheang MC,
    6. Koehler A,
    7. et al.
    Research-based PAM50 subtype predictor identifies higher responses and improved survival outcomes in HER2-positive breast cancer in the NOAH study. Clin Cancer Res 2014;20:511–21.
    OpenUrlAbstract/FREE Full Text
  96. 96.↵
    1. Kumarasamy V,
    2. Ruiz A,
    3. Nambiar R,
    4. Witkiewicz AK,
    5. Knudsen ES
    . Chemotherapy impacts on the cellular response to CDK4/6 inhibition: distinct mechanisms of interaction and efficacy in models of pancreatic cancer. Oncogene 2019;39:1831–45.
    OpenUrl
  97. 97.↵
    1. Salvador-Barbero B,
    2. Alvarez-Fernandez M,
    3. Zapatero-Solana E,
    4. El Bakkali A,
    5. Menendez MDC,
    6. Lopez-Casas PP,
    7. et al.
    CDK4/6 inhibitors impair recovery from cytotoxic chemotherapy in pancreatic adenocarcinoma. Cancer Cell 2020;37:340–53.
    OpenUrl
  98. 98.↵
    1. Cretella D,
    2. Fumarola C,
    3. Bonelli M,
    4. Alfieri R,
    5. La Monica S,
    6. Digiacomo G,
    7. et al.
    Pre-treatment with the CDK4/6 inhibitor palbociclib improves the efficacy of paclitaxel in TNBC cells. Sci Rep 2019;9:13014.
    OpenUrl
  99. 99.↵
    1. Witkiewicz AK,
    2. Cox D,
    3. Knudsen ES
    . CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer 2014;5:261–72.
    OpenUrlPubMed
  100. 100.↵
    1. Clark AS,
    2. McAndrew NP,
    3. Troxel A,
    4. Feldman M,
    5. Lal P,
    6. Rosen M,
    7. et al.
    Combination paclitaxel and palbociclib: results of a phase I trial in advanced breast cancer. Clin Cancer Res 2019;25:2072–9.
    OpenUrlAbstract/FREE Full Text
  101. 101.↵
    1. Knudsen ES,
    2. Pruitt SC,
    3. Hershberger PA,
    4. Witkiewicz AK,
    5. Goodrich DW
    . Cell cycle and beyond: exploiting new rb1 controlled mechanisms for cancer therapy. Trends Cancer 2019;5:308–24.
    OpenUrlCrossRefPubMed
  102. 102.↵
    1. Deng J,
    2. Wang ES,
    3. Jenkins RW,
    4. Li S,
    5. Dries R,
    6. Yates K,
    7. et al.
    CDK4/6 inhibition augments antitumor immunity by enhancing T-cell activation. Cancer Discov 2018;8:216–33.
    OpenUrlAbstract/FREE Full Text
  103. 103.↵
    1. Gandhi L,
    2. Rodriguez-Abreu D,
    3. Gadgeel S,
    4. Esteban E,
    5. Felip E,
    6. De Angelis F,
    7. et al.
    Pembrolizumab plus chemotherapy in metastatic non-small-cell lung cancer. N Engl J Med 2018;378:2078–92.
    OpenUrlCrossRefPubMed
  104. 104.↵
    1. Horn L,
    2. Mansfield AS,
    3. Szczesna A,
    4. Havel L,
    5. Krzakowski M,
    6. Hochmair MJ,
    7. et al.
    First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med 2018;379:2220–9.
    OpenUrlCrossRefPubMed
  105. 105.↵
    1. Ott PA,
    2. Hodi FS,
    3. Kaufman HL,
    4. Wigginton JM,
    5. Wolchok JD
    . Combination immunotherapy: a road map. J Immunother Cancer 2017;5:16.
    OpenUrlAbstract/FREE Full Text
  106. 106.↵
    1. Paz-Ares L,
    2. Luft A,
    3. Vicente D,
    4. Tafreshi A,
    5. Gumus M,
    6. Mazieres J,
    7. et al.
    Pembrolizumab plus chemotherapy for squamous non-small-cell lung cancer. N Engl J Med 2018;379:2040–51.
    OpenUrlCrossRefPubMed
  107. 107.↵
    1. Reck M,
    2. Rodriguez-Abreu D,
    3. Robinson AG,
    4. Hui R,
    5. Csoszi T,
    6. Fulop A,
    7. et al.
    Pembrolizumab versus chemotherapy for PD-L1-positive non-small-cell lung cancer. N Engl J Med 2016;375:1823–33.
    OpenUrlCrossRefPubMed
  108. 108.↵
    1. Schmid P,
    2. Adams S,
    3. Rugo HS,
    4. Schneeweiss A,
    5. Barrios CH,
    6. Iwata H,
    7. et al.
    Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med 2018;379:2108–21.
    OpenUrlCrossRefPubMed
  109. 109.↵
    1. North RJ
    . Cyclophosphamide-facilitated adoptive immunotherapy of an established tumor depends on elimination of tumor-induced suppressor T cells. J Exp Med 1982;155:1063–74.
    OpenUrlAbstract/FREE Full Text
  110. 110.↵
    1. Pfirschke C,
    2. Engblom C,
    3. Rickelt S,
    4. Cortez-Retamozo V,
    5. Garris C,
    6. Pucci F,
    7. et al.
    Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy. Immunity 2016;44:343–54.
    OpenUrlCrossRefPubMed
  111. 111.↵
    1. Suzuki E,
    2. Kapoor V,
    3. Jassar AS,
    4. Kaiser LR,
    5. Albelda SM
    . Gemcitabine selectively eliminates splenic Gr-1+/CD11b+ myeloid suppressor cells in tumor-bearing animals and enhances antitumor immune activity. Clin Cancer Res 2005;11:6713–21.
    OpenUrlAbstract/FREE Full Text
  112. 112.↵
    1. Zitvogel L,
    2. Apetoh L,
    3. Ghiringhelli F,
    4. Kroemer G
    . Immunological aspects of cancer chemotherapy. Nat Rev Immunol 2008;8:59–73.
    OpenUrlCrossRefPubMed
  113. 113.↵
    1. Lai AY,
    2. Sorrentino JA,
    3. Strum JC,
    4. Roberts PJ
    . Transient exposure of trilaciclib, a CDK4/6 inhibitor, modulates gene expression in tumor immune infiltrates to promote a pro-inflammatory tumor microenvironment. Cancer Res 2018;78:1752.
    OpenUrlCrossRef
  114. 114.↵
    1. Sorrentino JA,
    2. Lai AY,
    3. Strum JC,
    4. Roberts PJ
    . Trilaciclib (G1T28), a CDK4/6 inhibitor, enhances the efficacy of combination chemotherapy and immune checkpoint inhibitor treatment in preclinical models. Cancer Res 2017;77:5628.
    OpenUrlAbstract/FREE Full Text
Back to top
View this article with LENS

Open full page PDF
Article Alerts
Email Article
Citation Tools
Chemotherapy and CDK4/6 Inhibitors: Unexpected Bedfellows
Patrick J. Roberts, Vishnu Kumarasamy, Agnieszka K. Witkiewicz and Erik S. Knudsen
Mol Cancer Ther August 1 2020 (19) (8) 1575-1588; DOI: 10.1158/1535-7163.MCT-18-1161
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo

Jump to section

Advertisement