A systems mechanism for KRAS mutant allele-specific responses to targeted therapy. Sci Signal 2019 Sep 24;12(600)
Date
09/26/2019Pubmed ID
31551296Pubmed Central ID
PMC6864030DOI
10.1126/scisignal.aaw8288Scopus ID
2-s2.0-85072619385 (requires institutional sign-in at Scopus site) 36 CitationsAbstract
Cancer treatment decisions are increasingly guided by which specific genes are mutated within each patient's tumor. For example, agents inhibiting the epidermal growth factor receptor (EGFR) benefit many colorectal cancer (CRC) patients, with the general exception of those whose tumor includes a KRAS mutation. However, among the various KRAS mutations, that which encodes the G13D mutant protein (KRASG13D) behaves differently; for unknown reasons, KRASG13D CRC patients benefit from the EGFR-blocking antibody cetuximab. Controversy surrounds this observation, because it contradicts the well-established mechanisms of EGFR signaling with regard to RAS mutations. Here, we identified a systems-level, mechanistic explanation for why KRASG13D cancers respond to EGFR inhibition. A computational model of RAS signaling revealed that the biophysical differences between the three most common KRAS mutants were sufficient to generate different sensitivities to EGFR inhibition. Integrated computation with experimentation then revealed a nonintuitive, mutant-specific dependency of wild-type RAS activation by EGFR that is determined by the interaction strength between KRAS and the tumor suppressor neurofibromin (NF1). KRAS mutants that strongly interacted with and competitively inhibited NF1 drove wild-type RAS activation in an EGFR-independent manner, whereas KRASG13D weakly interacted with and could not competitively inhibit NF1 and, thus, KRASG13D cells remained dependent on EGFR for wild-type RAS activity. Overall, our work demonstrates how systems approaches enable mechanism-based inference in genomic medicine and can help identify patients for selective therapeutic strategies.
Author List
McFall T, Diedrich JK, Mengistu M, Littlechild SL, Paskvan KV, Sisk-Hackworth L, Moresco JJ, Shaw AS, Stites ECAuthor
Thomas Mcfall PhD Assistant Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAntineoplastic Agents, Immunological
Caco-2 Cells
Cell Line, Tumor
Cetuximab
Colorectal Neoplasms
ErbB Receptors
HCT116 Cells
Humans
Molecular Targeted Therapy
Mutation
Neurofibromatosis 1
Protein Binding
Proto-Oncogene Proteins p21(ras)
Signal Transduction
