Research ArticleCancer therapy

A systems mechanism for KRAS mutant allele–specific responses to targeted therapy

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Science Signaling  24 Sep 2019:
Vol. 12, Issue 600, eaaw8288
DOI: 10.1126/scisignal.aaw8288

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Refining precision medicine with systems biology

Patients with colorectal cancer (CRC) expressing the KRAS G13D mutant often respond to blockade of the growth factor receptor EGFR, whereas CRC patients with all other KRAS mutants do not. Because the reason why this treatment works is unclear in the context of known EGFR-RAS biology, clinical practice generally rejects its use for all KRAS-mutant CRC patients. However, McFall et al. used an integrated computational and biochemical approach to show that compared to other KRAS mutant proteins, KRAS G13D interacted too weakly with the protein NF1 to competitively inhibit it; therefore, wild-type RAS in KRAS G13D cells remains dependent upon EGFR for activation and for tumor growth. These findings reveal why precision medicine would benefit from a more systems-level rather than genomics-level analysis of patients.

Abstract

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.

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