Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints

• Type of Material: Article
• Authors: Yi Wen Kong, Massachusetts Institute of Technology; Erik Dreaden, Emory University; Sandra Morandell, Massachusetts Institute of Technology; Wen Zhou, Massachusetts Institute of Technology; Sanjeev S. Dhara, Massachusetts Institute of Technology; Ganapathy Sriram, Massachusetts Institute of Technology; Fred C. Lam, Massachusetts Institute of Technology; Jesse C. Patterson, Massachusetts Institute of Technology; Mohiuddin Quadir, Massachusetts Institute of Technology; Dinh Anh, Massachusetts Institute of Technology; Kevin E. Shopsowitz, Massachusetts Institute of Technology; Shohreh Varmeh, Massachusetts Institute of Technology; Omer H. Yilmaz, Massachusetts Institute of Technology; Stephen J. Lippard, Massachusetts Institute of Technology; H. Christian Reinhardt, Massachusetts Institute of Technology; Michael T. Hemann, Massachusetts Institute of Technology; Paula T. Hammond, Massachusetts Institute of Technology; Michael B. Yaffe, Massachusetts Institute of Technology
• Language: English
• Date: 2020-08-17
• Publisher: Nature Publishing Group
• Publication Version: Final Published Version
• Copyright Statement: © The Author(s) 2020.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1038/s41467-020-17958-z
• Title of Journal or Parent Work: Nature Communications
• Volume: 11
• Issue: 1
• Start Page: 4124
• End Page: 4124
• Grant/Funding Information: This work was supported by grants from the National Institutes of Health (R01-ES015339, R35-ES028374, R01-CA226898, and R01-GM104047 to M.B.Y., NIBIB 1F32EB017614 to E.C.D., CA034992 to S.J.L. and O.H.Y., AG045144, CA211184 to O.H.Y.),; Support was provided in part by the Koch Institute Support Grant (P30-CA14051) from the National Cancer Institute, and the MIT MRSEC Shared Experimental Facilities Grant (DMR-0819762) from the National Science Foundation.; Charles and Marjorie Holloway Foundation (M.B.Y.), the STARR Cancer Consortium (M.B.Y. and M.T.H.), the Misrock Foundation (Y.W.K.), the MIT Center for Precision Cancer Medicine (M.B.Y., M.T.H., Y.W.K., and F.C.L.), and the Mazumdar-Shaw International Oncology Fellowship (G.S.).; Ovarian Cancer Research Foundation (M.B.Y. and P.T.H.), the Breast Cancer Alliance (M.B.Y. and P.T.H.), US Department of Defense Congressionally Directed Medical Research Ovarian Cancer Research Program (P.T.H.; OCRP Teal Innovator Award; W81XWH-13-1-0151),
• Keywords: Inhibitor; DNA-Damage response; Kinase; Ovarian cancer; Multidisciplinary Sciences; Cross-link repair; Lung cancer; P53; Cisplatin; Protein; Tumors; Science & Technology; Science & Technology - Other Topics
• Research Categories: Health Sciences, Radiology; Engineering, Biomedical; Health Sciences, Oncology; Engineering, Chemical

Abstract

In response to DNA damage, a synthetic lethal relationship exists between the cell cycle checkpoint kinase MK2 and the tumor suppressor p53. Here, we describe the concept of augmented synthetic lethality (ASL): depletion of a third gene product enhances a pre-existing synthetic lethal combination. We show that loss of the DNA repair protein XPA markedly augments the synthetic lethality between MK2 and p53, enhancing anti-tumor responses alone and in combination with cisplatin chemotherapy. Delivery of siRNA-peptide nanoplexes co-targeting MK2 and XPA to pre-existing p53-deficient tumors in a highly aggressive, immunocompetent mouse model of lung adenocarcinoma improves long-term survival and cisplatin response beyond those of the synthetic lethal p53 mutant/MK2 combination alone. These findings establish a mechanism for co-targeting DNA damage-induced cell cycle checkpoints in combination with repair of cisplatin-DNA lesions in vivo using RNAi nanocarriers, and motivate further exploration of ASL as a generalized strategy to improve cancer treatment.