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

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2017 Jul 27

PMID 28746882

Citations 50

Authors

Grace R Anderson

Peter S Winter

Kevin H Lin

Daniel P Nussbaum

Merve Cakir

Elizabeth M Stein

Ryan S Soderquist

Lorin Crawford

Jim C Leeds

Rachel Newcomb

Priya Stepp

Catherine Yip

Suzanne E Wardell

Jennifer P Tingley

Moiez Ali

Mengmeng Xu

Meagan Ryan

Shannon J McCall

Autumn J McRee

Christopher M Counter

Channing J Der

Kris C Wood

Affiliations

Soon will be listed here.

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.

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