REV1–POLς Inhibition Enhances Cisplatin-Induced Cytotoxicity

Cancer cells frequently employ translesion synthesis (TLS) to bypass the replication fork–stalling effect of many chemotherapeutic agents, such as cisplatin, and thereby promote survival. Genetic depletion of REV1 or the catalytic subunit of Polς, mutagenic DNA polymerases involved in TLS, sensitizes cancer cells to DNA-damaging chemotherapeutic agents and suppresses the outgrowth of chemoresistant subpopulations. Wojtaszek, Chatterjee, Najeeb, and colleagues sought to identify small-molecule inhibitors of mutagenic TLS by targeting the interaction between REV1 and the REV7 (also known as MAD2L2) subunit of POLς, given the critical involvement of this conserved protein–protein interaction specifically in mutagenic TLS, but not accurate lesion bypass. Using a custom ELISA-based assay to screen ∼10,000 structurally diverse compounds, JH-RE-06 was identified as a potent inhibitor of the REV1–REV7 interaction. Further structural characterization revealed that JH-RE-06 binds the C-terminal domain (CTD) of REV1 and induces REV1 dimerization, which inhibits the interaction of the REV1 CTD with REV7. JH-RE-06 suppressed mutagenic TLS and enhanced the sensitivity of various human and mouse cancer cell lines to cisplatin as well as other DNA-damaging agents, resulting in decreased frequency of cisplatin-induced mutations and increased cytotoxicity. Of note, JH-RE-06 did not enhance chemosensitivity in Rev1^-/- mouse embryonic fibroblasts, indicating that the effect of JH-RE-06 is REV1-dependent. Furthermore, JH-RE-06 treatment augmented the efficacy of cisplatin in vivo, as combination treatment suppressed the growth of mouse melanoma xenografts and significantly improved overall survival. Collectively, this study supports further development of REV1 inhibitors as chemotherapeutic adjuvants that may limit the mutagenic evolution of chemoresistant cancer cell subpopulations.

Wojtaszek JL, Chatterjee N, Najeeb N, Ramos A, Lee M, Bian K, et al. A small molecule targeting mutagenic translesion synthesis improves chemotherapy. Cell 2019 Jun 6 [Epub ahead of print].

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