Title: Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer.
Authors: Vassel, Faye-Marie; Bian, Ke; Walker, Graham C; Hemann, Michael T
Published In Proc Natl Acad Sci U S A, (2020 11 17)
Abstract: 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.
PubMed ID: 33144509
MeSH Terms: Animals; Apoptosis/drug effects; Carcinoma, Non-Small-Cell Lung/drug therapy*; Carcinoma, Non-Small-Cell Lung/genetics; Carcinoma, Non-Small-Cell Lung/metabolism; Cell Line, Tumor; Cisplatin/pharmacology*; DNA Damage; DNA Repair; DNA-Binding Proteins/metabolism; DNA-Directed DNA Polymerase/metabolism; Drug Resistance, Neoplasm; Humans; Lung Neoplasms/drug therapy*; Lung Neoplasms/genetics; Lung Neoplasms/metabolism; Mad2 Proteins/antagonists & inhibitors*; Mad2 Proteins/metabolism; Mice; Mutagenesis; Tumor Cells, Cultured