REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks
Menée in vitro et à l'aide de xénogreffes de tumeurs sur des modèles murins, cette étude met en évidence un mécanisme par lequel JH-RE-06, un inhibiteur de la polymérase REV-1, augmente la réponse des cellules cancéreuses à la chimiothérapie en favorisant la survenue d'événements biologiques associés à la sénescence cellulaire
Mutagenic translesion synthesis (TLS) increases cell survival after DNA damage by bypassing lesions that normally block DNA replication but introduces mutations. In cancer cells, REV1/POLζ-dependent mutagenic TLS can contribute to intrinsic chemoresistance, while the mutations it introduces can underlie acquired chemoresistance. Interfering with this TLS pathway genetically or with the small molecule inhibitor JH-RE-06 has been shown to improve cisplatin chemotherapy by suppressing tumor growth and enhancing survival in mouse xenograft tumor models. Cisplatin chemotherapy commonly exerts its antitumor effects via DNA damage-mediated apoptosis. However, in two mouse xenograft models and four mammalian cell lines, the JH-RE-06 unexpectedly profoundly alters the biological response to cisplatin. Apoptosis is suppressed and surprisingly numerous hallmarks of senescence are induced prior to cell death.REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xenograft models, but the mechanism underlying this combinatorial effect is not known. We report that, unexpectedly, in two different mouse xenograft models and four human and mouse cell lines we examined in vitro cisplatin/JH-RE-06 treatment does not increase apoptosis. Rather, it increases hallmarks of senescence such as senescence-associated β-galactosidase, increased p21 expression, micronuclei formation, reduced Lamin B1, and increased expression of the immune regulators IL6 and IL8 followed by cell death. Moreover, although p-γ-H2AX foci formation was elevated and ATR expression was low in single agent cisplatin-treated cells, the opposite was true in cells treated with cisplatin/JH-RE-06. These observations suggest that targeting REV1 with JH-RE-06 profoundly affects the nature of the persistent genomic damage after cisplatin treatment and also the resulting physiological responses. These data highlight the potential of REV1/POLζ inhibitors to alter the biological response to DNA-damaging chemotherapy and enhance the efficacy of chemotherapy.All study data are included in the article and supporting information.