A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.
Journal Article (Journal Article)
Combinatorial inhibition of effector and feedback pathways is a promising treatment strategy for KRAS mutant cancers. However, the particular pathways that should be targeted to optimize therapeutic responses are unclear. Using CRISPR/Cas9, we systematically mapped the pathways whose inhibition cooperates with drugs targeting the KRAS effectors MEK, ERK, and PI3K. By performing 70 screens in models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers, we uncovered universal and tissue-specific sensitizing combinations involving inhibitors of cell cycle, metabolism, growth signaling, chromatin regulation, and transcription. Furthermore, these screens revealed secondary genetic modifiers of sensitivity, yielding a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers (CRCs) with clinical potential. Surprisingly, acquired resistance to combinations of growth signaling pathway inhibitors develops rapidly following treatment, but by targeting signaling feedback or apoptotic priming, it is possible to construct three-drug combinations that greatly delay its emergence.
Full Text
Duke Authors
- Counter, Christopher M.
- McCall, Shannon Jones
- Nussbaum, Daniel Philip
- Wardell, Suzanne E
- Wood, Kris Cameron
Cited Authors
- Anderson, GR; Winter, PS; Lin, KH; Nussbaum, DP; Cakir, M; Stein, EM; Soderquist, RS; Crawford, L; Leeds, JC; Newcomb, R; Stepp, P; Yip, C; Wardell, SE; Tingley, JP; Ali, M; Xu, M; Ryan, M; McCall, SJ; McRee, AJ; Counter, CM; Der, CJ; Wood, KC
Published Date
- July 25, 2017
Published In
Volume / Issue
- 20 / 4
Start / End Page
- 999 - 1015
PubMed ID
- 28746882
Pubmed Central ID
- PMC5567854
Electronic International Standard Serial Number (EISSN)
- 2211-1247
Digital Object Identifier (DOI)
- 10.1016/j.celrep.2017.07.006
Language
- eng
Conference Location
- United States