Cell Reports
Volume 20, Issue 4, 25 July 2017, Pages 999-1015
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A Landscape of Therapeutic Cooperativity in KRAS Mutant Cancers Reveals Principles for Controlling Tumor Evolution

https://doi.org/10.1016/j.celrep.2017.07.006Get rights and content
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Highlights

  • Scalable CRISPR screening identifies combination therapies for KRAS-driven cancers

  • Identification of tissue-specific and secondary modifiers of sensitivity

  • Clinical promise of combined MAPK and SRC inhibition in KRAS/PIK3CA mutant CRC

  • Key strategies to control the rapid evolution of resistance to two-body combinations

Summary

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

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

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These authors contributed equally