Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer.

Faye-Marie Vassel, Ke Bian, Graham C Walker, Michael T Hemann

Proceedings of the National Academy of Sciences of the United States of America 2020 Nov 17

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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.

Citation

Faye-Marie Vassel, Ke Bian, Graham C Walker, Michael T Hemann. Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer. Proceedings of the National Academy of Sciences of the United States of America. 2020 Nov 17;117(46):28922-28924