KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

Abstract

<i>KRAS</i> mutations occur in ∼35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. <i>KRAS</i> mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render <i>KRAS</i>-mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that <i>KRAS</i> G13-mutated cancer cells are frequently comutated with <i>NF1</i> GAP but <i>NF1</i> is rarely mutated in cancers with <i>KRAS</i> codon 12 or 61 mutations. Neurofibromin protein (encoded by the <i>NF1</i> gene) hydrolyzes GTP directly in complex with KRAS G13D, and <i>KRAS</i> G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Structures of the wild type and G13D mutant of KRAS in complex with neurofibromin (RasGAP domain) provide the structural basis for neurofibromin-mediated GTP hydrolysis. These results reveal that KRAS G13D is responsive to neurofibromin-stimulated hydrolysis and suggest that a subset of <i>KRAS</i> G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.