Tissue-Specific Oncogenic Activity of KRASA146T
Open accessPublished version of a preprint
Abstract
KRAS is the most frequently mutated oncogene. The incidence of specific KRAS alleles varies between cancers from different sites, but it is unclear whether allelic selection results from biological selection for specific mutant KRAS proteins. We used a cross-disciplinary approach to compare KRASG12D, a common mutant form, and KRASA146T, a mutant that occurs only in selected cancers. Biochemical and structural studies demonstrated that KRASA146T exhibits a marked extension of switch 1 away from the protein body and nucleotide binding site, which activates KRAS by promoting a high rate of intrinsic and guanine nucleotide exchange factor–induced nucleotide exchange. Using mice genetically engineered to express either allele, we found that KRASG12D and KRASA146T exhibit distinct tissue-specific effects on homeostasis that mirror mutational frequencies in human cancers. These tissue-specific phenotypes result from allele-specific signaling properties, demonstrating that context-dependent variations in signaling downstream of different KRAS mutants drive the KRAS mutational pattern seen in cancer. Significance: Although epidemiologic and clinical studies have suggested allele-specific behaviors for KRAS, experimental evidence for allele-specific biological properties is limited. We combined structural biology, mass spectrometry, and mouse modeling to demonstrate that the selection for specific KRAS mutants in human cancers from different tissues is due to their distinct signaling properties. See related commentary by Hobbs and Der, p. 696. This article is highlighted in the In This Issue feature, p. 681
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KRAS G12R, G13D, Q61H, Q61L, and A146T mutations have increased intrinsic exchange relative to wildtype, but G12C and G12V do not display large changes.
“KRAS G12R, G13D, Q61H, Q61L, and A146T mutations have increased intrinsic exchange relative to wildtype, but G12C and G12V do not display large changes [4,29,30,31,32].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [29]
The Results section, “A146T promotes nucleotide exchange” (page unavailable), reports that KRAS A146T has an approximately 12-fold higher intrinsic GDP dissociation rate than wildtype. The passages found do not establish the claimed exchange behavior of G12R, G13D, Q61H, Q61L, G12C, or G12V. (LLM, conf=0.87)
Experimental — accuracy not yet measuredThe variation in activating alleles across cancers indicates possible differences in signaling behavior of mutant proteins that exploit the environment of the specific cellular context.
“indicating possible differences in signaling behavior of the mutant proteins that exploit the environment of the specific cellular context3,4”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [4]
Additional biochemical, structural, and signaling distinctions have been identified between different mutant KRAS alleles, including between those at the same amino acid position.
“Additional biochemical, structural, and signaling distinctions have been identified between different mutant alleles, including between those at the same amino acid position4,8,13–20.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [4]
Forced expression of KRAS A146T in mouse pancreas does not induce pancreatic intraepithelial neoplasia.
“forced expression of KRAS A146T in mouse pancreas does not induce pancreatic intraepithelial neoplasia4”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [4]
146 mutations do not alter the rate of GTP hydrolysis, but cause hyperactivation through an increased rate of GDP exchange.
“146 mutations do not alter the rate of GTP hydrolysis, but cause hyperactivation through an increased rate of GDP exchange4,10–12”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [4]
The activating alleles found in KRAS vary substantially across cancers.
“the activating alleles found in KRAS vary substantially across cancers”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [4]
Mutant forms of KRAS produce distinct molecular and cellular phenotypes that are largely dependent upon the tissue context.
“mutant forms of KRAS produce distinct molecular and cellular phenotypes that are largely dependent upon the tissue context4,78,79”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [4]
Specific KRAS variants can have tissue-specific oncogenic effects and exhibit allele-specific therapeutic vulnerabilities in downstream effector pathways.
“The implication of these unusual variants is that specific KRAS variants can have tissue-specific oncogenic effects and exhibit allele-specific therapeutic vulnerabilities in downstream effector pathways.”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [90]
A146T and Q61H KRAS mutations remain sensitive to pan-KRAS inhibitors and degraders targeting the OFF form of KRAS, whereas KRAS G12R may require KRAS ON drugs.
“While A146T and Q61H mutations in KRAS remain sensitive to pan-KRAS inhibitors and degraders targeting the “OFF” form of KRAS, this appears not the case for the KRAS G12R mutant which could require KRAS “ON” drugs.”
From Expanding the Reach of Precision Oncology by Drugging All <i>KRAS</i> Mutants (2022) · cites this paper as [90]
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References 55 · Cited by 197
- Authors
- Poulin, E. J., Bera, A. K., Lu, J., Lin, Y.-J., Strasser, S. D., Paulo, J. A., Huang, T. Q., Morales, C., Yan, W., Cook, J., Nowak, J. A., Brubaker, D. K., Joughin, B. A., Johnson, C. W., DeStefanis, R. A., Ghazi, P. C., Gondi, S., Wales, T. E., Iacob, R. E., Bogdanova, L., Gierut, J. J., Li, Y., Engen, J. R., Perez-Mancera, P. A., Braun, B. S., Gygi, S. P., Lauffenburger, D. A., Westover, K. D., & Haigis, K. M.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- The University of Texas Southwestern Medical Center (US)
- 6Department of Cell Biology, Harvard Medical School, Boston, Massachusetts.
- University of California, San Francisco (US)
- Brigham and Women's Hospital (US)
- Massachusetts Institute of Technology (US)
- Northeastern University (US)
- 11Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
- Harvard University (US)
- Corresponding author
- Westover, Kenneth D.
- Haigis, Kevin M.
- ORCID
- Poulin, Emily J.
- Bera, Asim K.
- Lin, Yi-Jang
- Paulo, Joao A.
- Morales, Carolina
- Yan, Wei
- Cook, Joshua
- Nowak, Jonathan A.
- Brubaker, Douglas K.
- Joughin, Brian A.
- Johnson, Christian W.
- DeStefanis, Rebecca A.
- Ghazi, Phaedra C.
- Gondi, Sudershan
- Wales, Thomas E.
- Iacob, Roxana E.
- Li, Yina
- Engen, John R.
- Braun, Benjamin S.
- Gygi, Steven P.
- Lauffenburger, Douglas A.
- Westover, Kenneth D.
- Haigis, Kevin M.
- Venue
- Cancer Discovery
- Published
- 2019-06-01
- Volume
- 9
- Issue
- 6
- Pages
- 738-755
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC6548671
- OpenAlex
- W2926958318
- Cited by
- 197
- References
- 55
- Citations by year
- 2026: 20 · 2025: 28 · 2024: 24 · 2023: 21 · 2022: 35 · 2021: 31 · 2020: 23 · 2019: 15
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
- Funders
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (R01CA178017, R01CA195744, U01CA215798, R01CA173085, P30CA082103)
- American Cancer SocietyAmerican Cancer Society (ACS)
- National Science FoundationNational Science Foundation (NSF) (1122374)
- Landry Cancer Biology Consortium
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney DiseasesHHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (K01DK098285)
- U.S. Department of DefenseU.S. Department of Defense (DOD) (W81XWH-16-1-0106)
- Cancer Prevention and Research Institute of TexasCancer Prevention and Research Institute of Texas (CPRIT) (RP170373)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Tyrosine Phosphatases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Keywords
- KRAS, KRAS G12D, oncogenic activity, guanine nucleotide exchange
- MeSH terms
- Alleles, Cell Transformation, Neoplastic, Humans, Models, Molecular, Mutation, Neoplasms, Oncogenes, Organ Specificity, Phenotype, Protein Conformation, Structure-Activity Relationship, Proto-Oncogene Proteins p21(ras), Proteome, Proteomics
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