Article Figures & Data
Figures
- Figure 1.
Targeting PIM kinases to overcome therapeutic resistance. A, PIM kinases promote resistance to many classes of anticancer therapy by activating signaling pathways that increase angiogenesis, proliferation, survival, metastasis, and immune evasion. B, Small-molecule PIM inhibitors increase the efficacy of chemotherapy and targeted agents by inhibiting various signaling pathways used by cancer cells to escape therapy.
Tables
- Table 1.
PIM kinases promote resistance to anticancer therapies.
Drug class Mechanism of resistance Chemotherapy Regulates drug transporters Blocks chemotherapy-induced oxidative stress Radiotherapy Decreases apoptosis PI3K/mTOR inhibitors Activates downstream targets Blocks ROS generated by PI3K inhibitors EGFR inhibitors Activates downstream targets Blocks inhibitory factors Activates MET signaling MET inhibitors Promotes cell protective, antiapoptotic signaling Increases protein translation FLT3-ITD inhibitors Supports mitochondrial integrity Antiangiogenic therapies Upregulated in hypoxia to promote secretion of proangiogenic factors Abbreviation: MET: c-MET oncogene.
- Table 2.
PIM inhibitors in clinical trials.
Drug Clinical trial number Phase Disease Result INCB053914 NCT02587598 (85) I/II AML, high-risk MDS, MDS/MPN, multiple myeloma, lymphoma, and other lymphoproliferative neoplasms Preliminary safety (AEs reversible with drug interruption/dose reduction) Estimated completion: 2021 INCB053914 with pomalidomide and dexamethasone NCT04355039 (86) II Refractory/relapsed multiple myeloma Not yet recruiting INCB053914 with INCB050465 (PI3K inhibitor) NCT03688152 (84) I Diffuse large B-cell lymphoma Not yet recruiting TP-3654 NCT03715504 (87) I Advanced solid tumors Preliminary safety (no DLTs, no grade >3 AEs); prolonged SD TP-3654 NCT04176198 (88) I Myelofibrosis Ongoing (estimated completion 2022) SEL24/MEN1703 NCT03008187 (89) I/II AML Acceptable safety profile, five DLTs; one CR, one CRi AZD1208 NCT01489722 (82) I AML Serious AEs in 23 patients (discontinued in 8) and DLTs in 5; no clinical response AZD1208 NCT01588548 (82) I Advanced solid malignancies Serious AEs in 8 patients and DLTs in 4; best response SD ≥ 6 weeks (13 patients; ORR, 0%) SGI-1776 NCT01239108 (90) I Relapsed/refractory leukemia Withdrawn due to cardiac QTc prolongation SGI-1776 NCT00848601 (91) I Prostate cancer/Hodgkin lymphoma Withdrawn due to cardiac QTc prolongation PIM447 NCT01456689 (81) I Relapsed/refractory multiple myeloma Hematologic grade 3/4 AEs; disease control rate of 72.2%, ORR of 8.9% PIM447 with ruxolitinib and LEE011 NCT02370706 (92) Ib Myelofibrosis Ongoing (estimated completion 2020) CXR1002 Not registered (93) I Advanced refractory solid tumors MTD not reached SD > 12 weeks in 8 patients Abbreviations: AE, adverse event; CR, complete response; CRi, complete response with incomplete recovery of platelet count; DLT, dose-limiting toxicity; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasm; ORR, overall response rate; SD, stable disease.
Volume 20, Issue 1
