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

Autor: Kong YW; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Dreaden EC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Department of Pediatrics, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, GA, 30322, USA., Morandell S; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Molecular Health GmbH, 69115, Heidelberg, Germany., Zhou W; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Dhara SS; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Sriram G; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Lam FC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Division of Neurosurgery, Hamilton General Hospital, McMaster University Faculty of Health Sciences, Hamilton, ON, L8L 2X2, Canada., Patterson JC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Quadir M; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Coatings and Polymeric Materials, North Dakota State University, Fargo, USA., Dinh A; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Shopsowitz KE; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Varmeh S; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Yilmaz ÖH; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Lippard SJ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Department of Chemistry, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Reinhardt HC; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Clinic I of Internal Medicine, University Hospital Cologne, Cologne, Germany.; Cologne Excellence Cluster in Cellular Stress Response in Aging-Associated Disorders (CECAD), University of Cologne, Cologne, Germany.; Center for Molecular Medicine Cologne, University of Cologne, Cologne, Germany., Hemann MT; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA., Hammond PT; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. hammond@mit.edu.; Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. hammond@mit.edu., Yaffe MB; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. myaffe@mit.edu.; Center for Precision Cancer Medicine, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. myaffe@mit.edu.; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. myaffe@mit.edu.; Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA. myaffe@mit.edu.; Divisions of Surgical Oncology, Trauma, and Surgical Critical Care, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA. myaffe@mit.edu.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2020 Aug 17; Vol. 11 (1), pp. 4124. Date of Electronic Publication: 2020 Aug 17.
DOI: 10.1038/s41467-020-17958-z
Abstrakt: 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.
Databáze: MEDLINE