Biochemical and structural analysis of common cancer-associated KRAS mutations

John C. Hunter, Anuj Manandhar, Martin A. Carrasco, Deepak Gurbani, Sudershan Gondi, Kenneth D. Westover

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

KRAS mutations are the most common genetic abnormalities in cancer, but the distribution of specific mutations across cancers and the differential responses of patients with specific KRAS mutations in therapeutic clinical trials suggest that different KRAS mutations have unique biochemical behaviors. To further explain these high-level clinical differences and to explore potential therapeutic strategies for specific KRAS isoforms, we characterized the most common KRAS mutants biochemically for substrate binding kinetics, intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activities, and interactions with the RAS effector, RAF kinase. Of note, KRAS G13D shows rapid nucleotide exchange kinetics compared with other mutants analyzed. This property can be explained by changes in the electrostatic charge distribution of the active site induced by the G13Dmutation as shown by Xray crystallography. High-resolution X-ray structures are also provided for the GDP-bound forms of KRAS G12V, G12R, and Q61L and reveal additional insight. Overall, the structural data and measurements, obtained herein, indicate that measurable biochemical properties provide clues for identifying KRASdriven tumors that preferentially signal through RAF. Implications: Biochemical profiling and subclassification of KRAS-driven cancers will enable the rational selection of therapies targeting specific KRAS isoforms or specific RAS effectors.

Original languageEnglish (US)
Pages (from-to)1325-1335
Number of pages11
JournalMolecular Cancer Research
Volume13
Issue number9
DOIs
StatePublished - Sep 1 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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