Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer
Year: 2020
Type: article
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.
Language: English
Topic: DNA Repair Mechanisms
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Massachusetts Institute of Technology, Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, National Institutes of Health, Ludwig Center for Molecular Oncology, Ludwig Center at Harvard, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Environmental Health Sciences
Awards: G1222265720, Mechanism of Eukaryotic Environmental Mutagenesis, Identifying and targeting evolutionary trajectories in cancer, G2360436881, MIT Center for Environmental Health Sciences, Training Grant in Environmental Toxicology, G4469701415, G4774430914, G6879439366, RNA-Binding Proteins as Molecular Integrators that Control the Response of HGSOC to Ant-Cancer Therapies, Mechanism of Eukaryotic Environmental Mutagenesis, Pre-Doctoral Training in Biological Sciences, G8824228350, G9000300833, Cancer Center Support (Core) Grant
OpenAlex ID: W3095757372