RT Journal Article
SR Electronic
T1 A Systems Mechanism for KRAS Mutant Allele Specific Responses to Targeted Therapy
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 491621
DO 10.1101/491621
A1 Thomas McFall
A1 Jolene K. Diedrich
A1 Meron Mengistu
A1 Stacy L. Littlechild
A1 Kendra V. Paskvan
A1 Laura Sisk-Hackworth
A1 James J. Moresco
A1 Andrey S. Shaw
A1 Edward C. Stites
YR 2018
UL http://biorxiv.org/content/early/2018/12/10/491621.abstract
AB 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.