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

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.

• Authors: Faye-Marie Vassel, Ke Bian, Graham C Walker, Michael T Hemann
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 117 Issue 46 Pg. 28922-28924 (11 17 2020) ISSN: 1091-6490 [Electronic] United States
• PMID: 33144509 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• MAD2L2 protein, human
• Mad2 Proteins
• Mad2l2 protein, mouse
• DNA-Directed DNA Polymerase
• Cisplatin

Topics

• Animals
• Apoptosis (drug effects)
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics, 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, genetics, metabolism)
• Mad2 Proteins (antagonists & inhibitors, metabolism)
• Mice
• Mutagenesis
• Tumor Cells, Cultured