DOI: 10.1101/491621Dec 10, 2018Paper

A Systems Mechanism for KRAS Mutant Allele Specific Responses to Targeted Therapy

BioRxiv : the Preprint Server for Biology
Thomas McFallEdward C Stites

Abstract

A well-established genotype to phenotype relationship in genomic medicine is that activating KRAS mutations indicate resistance to anti-EGFR agents. We used a computational model of Ras signaling to investigate a confusing exception to this relationship whereby colorectal cancers with one specific, constitutively-active, mutant, KRAS G13D, respond to anti-EGFR agents. Our computational simulations of the biochemical processes that regulate Ras suggest EGFR inhibition reduces wild-type Ras activation in KRAS G13D mutant cancer cells more than in other KRAS mutant cancer cells. The model also reveals a non-intuitive, mutant-specific, dependency of wild-type Ras activation on EGFR. This dependency is determined by the interaction strength between a KRAS mutant and tumor suppressor neurofibromin. Our prospective experiments confirm this mechanism that arises from the systems-level regulation of Ras pathway signaling. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine.

Related Concepts

Epidermal Growth Factor Receptor
Tumor Suppressor Genes
Mutant
Simulation
Genomics
Regulation of Biological Process
Ras Signaling Pathway
Colorectal Cancer
KRAS gene
KRAS wt Allele

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