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

Grace R Anderson1, Peter S Winter2, Kevin H Lin1

  • 1Department of Pharmacology and Cancer Biology, Duke University, Durham, NC 27710, USA.

Cell Reports
|July 27, 2017
PubMed

Insights

Targeting KRAS mutant cancers with drug combinations shows promise. This study mapped cooperating pathways using CRISPR screens, identifying new strategies to overcome resistance and improve treatment for colorectal, lung, ovarian, and pancreas cancers.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Combinatorial inhibition of effector and feedback pathways is a key strategy for KRAS mutant cancers.
  • Identifying optimal pathway targets for therapeutic response remains a challenge.

Purpose of the Study:

  • To systematically map pathways that cooperate with MEK, ERK, and PI3K inhibitors in KRAS mutant cancers.
  • To uncover universal and tissue-specific drug combinations and identify genetic modifiers of sensitivity.
  • To develop novel combination therapies, including three-drug regimens, to overcome acquired resistance.

Main Methods:

  • Utilized CRISPR/Cas9 screening across 70 models of KRAS mutant colorectal, lung, ovarian, and pancreas cancers.
  • Investigated combinatorial effects of inhibiting KRAS effectors (MEK, ERK, PI3K) with other pathway inhibitors.
  • Analyzed genetic modifiers of drug sensitivity and resistance mechanisms.

Main Results:

  • Discovered universal and tissue-specific sensitizing combinations targeting cell cycle, metabolism, growth signaling, chromatin, and transcription.
  • Identified a SRC inhibitor-based combination therapy for KRAS/PIK3CA double-mutant colorectal cancers with clinical potential.
  • Demonstrated that three-drug combinations targeting signaling feedback or apoptotic priming can significantly delay acquired resistance.

Conclusions:

  • Systematic pathway mapping reveals diverse combinatorial strategies for KRAS mutant cancers.
  • Targeting specific genetic modifiers and feedback loops offers a path towards overcoming drug resistance.
  • Developed novel combination therapies with potential for clinical application in KRAS-driven malignancies.
Keywords:
BIMCRISPR/Cas9KRASPIK3CASRCapoptosisdrug resistancepooled screeningsynthetic lethality

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