Enhancing chemotherapy response through augmented synthetic lethality by co-targeting nucleotide excision repair and cell-cycle checkpoints
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Aug 17, 2020
- Source ID
- 10.1038/s41467-020-17958-z
Entities
People
- Anh Dinh
- Erik C Dreaden
- Fred C Lam
- Ganapathy Sriram
- H. Christian Reinhardt
- Jesse C. Patterson
- Kevin E. Shopsowitz
- Michael B Yaffe
- Michael T. Hemann
- Mohiuddin Quadir
- Paula T. Hammond
- Sandra Morandell
- Sanjeev S Dhara
- Shohreh Varmeh
- Stephen J. Lippard
- Wen Zhou
- Yi Wen Kong
- Ömer H. Yılmaz
Organizations
- Congressionally Directed Medical Research Programs
- National Cancer Institute
- National Institute of Biomedical Imaging and Bioengineering
- National Institute of Environmental Health Sciences
- National Institute of General Medical Sciences
- Ovarian Cancer Research Foundation
- United States Department of Health and Human Services