Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer
Menée à l'aide d'un modèle murin de cancer du poumon non à petites cellules résistant à la chimiothérapie, cette étude démontre que la perte de l'expression de REV7, un gène impliqué dans la réparation des cassures double-brin de l'ADN, améliore la sensibilité des cellules cancéreuses au cisplatine
Mutagenic translesion synthesis (TLS) allows cells to increase their survival after DNA damage by bypassing lesions that normally block DNA replication but at the cost of introducing mutations. 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. Deleting Rev7, which is a component of both the TLS machinery and a complex that regulates the choice of double-strand break repair pathways, strikingly potentiates cisplatin chemotherapy in a lung cancer model. Moreover, while cisplatin monotherapy resulted in tumor cell apoptosis, Rev7 deletion promoted a cisplatin-induced senescence phenotype, suggesting that targeting Rev7 is an attractive strategy to improve chemotherapy.Cisplatin is a standard of care for lung cancer, yet platinum therapy rarely results in substantial tumor regression or a dramatic extension in patient survival. Here, we examined whether targeting Rev7 (also referred to as Mad2B, Mad2L2, and FANCV), a component of the translesion synthesis (TLS) machinery, could potentiate the action of cisplatin in non-small cell lung cancer (NSCLC) treatment. Rev7 loss led to an enhanced tumor cell sensitivity to cisplatin and dramatically improved chemotherapeutic response in a highly drug-resistant mouse model of NSCLC. While cisplatin monotherapy resulted in tumor cell apoptosis, Rev7 deletion promoted a cisplatin-induced senescence phenotype. Moreover, Rev7 deficiency promoted greater cisplatin sensitivity than that previously shown following targeting of other Pol ζ-proteins, suggesting that Pol ζ-dependent and -independent roles of Rev7 are relevant to cisplatin response. Thus, targeting Rev7 may represent a unique strategy for altering and enhancing chemotherapeutic response.All study data are included in the article and supporting information.