Mechanisms of acquired resistance to BET-PROTACs
Zhang et al. Page 1302
PROTACs are bifunctional molecules that hijack endogenous E3 ubiquitin ligases to induce degradation of protein of interest. With the PROTAC technology progressing rapidly towards therapeutic applications, it would be important to understand whether and how resistance to these novel agents may emerge. Using BET-PROTACs as a model system, Zhang and colleagues demonstrate that resistance to both VHL- and CRBN-based PROTACs was primarily caused by genomic alterations that compromise core components of the relevant E3 ligase complexes. This study reveals a novel resistance mechanism distinct from current targeted therapies and lay the foundation for future investigations.
Alpha-particle therapy for the treatment of neuroblastoma
Makvandi et al. Page 1195
Neuroblastomas are highly radiosensitive, which opened the door for the development of beta-emitting radiotherapeutics to treat tumors. Beta particles are limited, however, in their ability to introduce DNA damage to single cells or micrometastatic clusters. Alpha particles deliver high amounts of linear energy transfer, depositing their energy over a short path-lengths. Makvandi and colleagues designed a PARP-1-targeted, astatine-211 (211At)-conjugated radiopharmaceutical ([211At]MM4). [211At]MM4 showed a durable anti-tumor response in a murine neuroblastoma xenograft. Moreover, there was a unique drug target up-regulation that adds a benefit to fractionated doses of [211At]MM4. Taken together, the study demonstrates the capability of targeting chromatin with alpha emitters through PARP-1 with broad implications in cancer therapy.
Preclinical characterization of NAE inhibitor TAS4464
Yoshimura et al. Page 1205
NEDD8 conjugation is a post-translational protein modification, and its regulation is related to cancer growth and survival. Yoshimura and colleagues reported the biological activities of TAS4464, a novel highly potent NAE selective inhibitor. TAS4464 inactivated the cullin-RING E3 ubiquitin ligases and consequently accumulated its substrates, such as p21, CDT1, and phosphorylated-IkBα. Weekly administration of TAS4464 showed prominent antitumor activities in human tumor xenograft models with a long duration of action within tumors. The use of longer-acting NAE inhibitor in intermittent dosing regimens has the potential to exert antitumor activity while minimizing the toxicity with less exposure on normal tissues.
Dual role of TGFβ in CRC
Siraj et al. Page 1312
In Saudi Arabia, colorectal cancer (CRC) presents the number one cancer affecting males and is marked by tumors that are more aggressive and present with higher stages. To combat this, Siraj and colleagues investigated the role of the Smad4/TGFβ axis in generating aggressive phenotypes in Saudi CRC. They demonstrate that Smad4 alterations can identify patients at a late stage (Dukes' C CRC) and at a high risk for recurrence after surgery and 5-FU chemotherapy. Furthermore, they outline the dependence of chemoresistance in Smad-deficient cells on KLF5 in TGFβ-stimulated conditions, highlighting the potential of KLF5 inhibition in CRC treatment.
- ©2019 American Association for Cancer Research.
Volume 18, Issue 7
