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Title: KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis

Abstract

KRAS mutations occur in ~35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. KRAS mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render KRAS-mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that KRAS G13-mutated cancer cells are frequently comutated with NF1 GAP but NF1 is rarely mutated in cancers with KRAS codon 12 or 61 mutations. Neurofibromin protein (encoded by the NF1 gene) hydrolyzes GTP directly in complex with KRAS G13D, and KRAS G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Furthermore, 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 KRAS G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.

Authors:
; ; ; ; ; ORCiD logo;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC); National Cancer Institute (NCI); National Institutes of Health (NIH); National Institute of General Medical Sciences (NIGMS)
OSTI Identifier:
1570474
Alternate Identifier(s):
OSTI ID: 1576002
Grant/Contract Number:  
AC02-06CH11357; HHSN261200800001E; P41 GM103403
Resource Type:
Published Article
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Name: Proceedings of the National Academy of Sciences of the United States of America Journal Volume: 116 Journal Issue: 44; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; KRAS; G13D; NF1; EGFR; GTPase

Citation Formats

Rabara, Dana, Tran, Timothy H., Dharmaiah, Srisathiyanarayanan, Stephens, Robert M., McCormick, Frank, Simanshu, Dhirendra K., and Holderfield, Matthew. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. United States: N. p., 2019. Web. doi:10.1073/pnas.1908353116.
Rabara, Dana, Tran, Timothy H., Dharmaiah, Srisathiyanarayanan, Stephens, Robert M., McCormick, Frank, Simanshu, Dhirendra K., & Holderfield, Matthew. KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis. United States. doi:10.1073/pnas.1908353116.
Rabara, Dana, Tran, Timothy H., Dharmaiah, Srisathiyanarayanan, Stephens, Robert M., McCormick, Frank, Simanshu, Dhirendra K., and Holderfield, Matthew. Mon . "KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis". United States. doi:10.1073/pnas.1908353116.
@article{osti_1570474,
title = {KRAS G13D sensitivity to neurofibromin-mediated GTP hydrolysis},
author = {Rabara, Dana and Tran, Timothy H. and Dharmaiah, Srisathiyanarayanan and Stephens, Robert M. and McCormick, Frank and Simanshu, Dhirendra K. and Holderfield, Matthew},
abstractNote = {KRAS mutations occur in ~35% of colorectal cancers and promote tumor growth by constitutively activating the mitogen-activated protein kinase (MAPK) pathway. KRAS mutations at codons 12, 13, or 61 are thought to prevent GAP protein-stimulated GTP hydrolysis and render KRAS-mutated colorectal cancers unresponsive to epidermal growth factor receptor (EGFR) inhibitors. We report here that KRAS G13-mutated cancer cells are frequently comutated with NF1 GAP but NF1 is rarely mutated in cancers with KRAS codon 12 or 61 mutations. Neurofibromin protein (encoded by the NF1 gene) hydrolyzes GTP directly in complex with KRAS G13D, and KRAS G13D-mutated cells can respond to EGFR inhibitors in a neurofibromin-dependent manner. Furthermore, 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 KRAS G13-mutated colorectal cancers that are neurofibromin-competent may respond to EGFR therapies.},
doi = {10.1073/pnas.1908353116},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
number = 44,
volume = 116,
place = {United States},
year = {2019},
month = {10}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record
DOI: 10.1073/pnas.1908353116

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