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.
- 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. https://doi.org/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. https://doi.org/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}
}
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https://doi.org/10.1073/pnas.1908353116
https://doi.org/10.1073/pnas.1908353116
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Cited by: 4 works
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Figures / Tables:
Fig. 1: KRAS G13D CRC cells are sensitive to NF1-mediated GTP hydrolysis. (A) Total number of mutations per sample in KRAS G12- and G13-mutated COAD from TCGA cancer samples (P = 0.018). (B) Mutational burden comparing KRAS codon 12 and codon 13 mutations with mismatch repair mutations and microsatellite instabilitymore »
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