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Cell Rep. 2017 Jul 25;20(4):999-1015. doi: 10.1016/j.celrep.2017.07.006.

A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution.

Author information

1
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.
2
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA; Program in Genetics and Genomics, Duke University, Durham, NC 27710, USA.
3
Department of Surgery, Duke University, Durham, NC 27710, USA.
4
Department of Statistics, Duke University, Durham, NC 27710, USA.
5
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.
6
Department of Pathology, Duke University, Durham, NC 27710, USA.
7
Department of Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
8
Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA. Electronic address: kris.wood@duke.edu.

Abstract

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.

KEYWORDS:

BIM; CRISPR/Cas9; KRAS; PIK3CA; SRC; apoptosis; drug resistance; pooled screening; synthetic lethality

PMID:
28746882
PMCID:
PMC5567854
DOI:
10.1016/j.celrep.2017.07.006
[Indexed for MEDLINE]
Free PMC Article

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