REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks

• DOI: 10.1073/pnas.2016064117
• Publication Date: 2020-11-10T01:30:32Z
• Authors: Nimrat Chatterjee; Matthew A. Whitman; Cynthia A. Harris; Sophia M. Min; Oliver Jonas; Evan C. Lien; Alba Luengo; Matthew G. Vander...; Jiyong Hong; Pei Zhou; Michael T. Hemann; Graham C. Walker
• Keywords: Senescence

Significance Mutagenic translesion synthesis (TLS) increases cell survival after DNA damage by bypassing lesions that normally block replication but introduces mutations. In cancer cells, REV1/POLζ-dependent mutagenic TLS can contribute to intrinsic chemoresistance, while the mutations it underlie acquired chemoresistance. Interfering with this pathway genetically or small molecule inhibitor JH-RE-06 has been shown improve cisplatin chemotherapy suppressing tumor growth and enhancing in mouse xenograft models. Cisplatin commonly exerts its antitumor effects via damage-mediated apoptosis. However, two models four mammalian lines, unexpectedly profoundly alters biological response cisplatin. Apoptosis is suppressed surprisingly numerous hallmarks of senescence are induced prior death.