KRAS Alleles: The Devil Is in the Detail
Open accessAbstract
KRAS is the most frequently mutated oncogene in cancer and KRAS mutation is commonly associated with poor prognosis and resistance to therapy. Since the KRAS oncoprotein is, as yet, not directly druggable, efforts to target KRAS mutant cancers focus on identifying vulnerabilities in downstream signaling pathways or in stress response pathways that are permissive for strong oncogenic signaling. One aspect of KRAS biology that is not well appreciated is the potential biological differences between the many distinct KRAS activating mutations. This review draws upon insights from both clinical and experimental studies to explore similarities and differences among KRAS alleles. Historical and emerging evidence supports the notion that the specific biology related to each allele might be exploitable for allele-specific therapy.
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G12D and G12V mutations are the most common in pancreatic ductal adenocarcinoma, followed by G12R.
“G12D and G12V mutations are the most common in PDAC, followed by G12R.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [32]
The Epidemiology of KRAS Alleles section identifies G12D as the most common allele in PDAC. The KRAS Allelic Variation section says codon 12 mutations predominate, but the text in our copy does not establish that G12V is second most common or that G12R follows it in PDAC. (LLM, conf=0.84)
Experimental — accuracy not yet measuredKRAS 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 [32]
The Biochemistry of KRAS Alleles section (page unavailable) says codon 13 mutants increase intrinsic exchange and A146 mutations markedly promote exchange, supporting the G13D and A146T portions at the codon level. It also says most codon 12 mutants do not change exchange, broadly consistent with G12C and G12V. It does not establish increased exchange for G12R, Q61H, or Q61L; it discusses Q61 mutants chiefly in terms of reduced hydrolysis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredG12C and G12V mutations are predominant in lung adenocarcinomas with smoking-associated mutational signatures.
“G12C and G12V mutations are predominant in lung adenocarcinomas with smoking-associated mutational signatures [30,32].”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [32]
The “KRAS Allelic Variation” section says G12C and G12V are the most frequent KRAS mutations in non-small cell lung cancer and arise from a classical smoking-induced transversion. It does not establish their predominance specifically in lung adenocarcinomas with smoking-associated mutational signatures. (LLM, conf=0.85)
Experimental — accuracy not yet measuredSpecific KRAS mutations show characteristic patterns of tissue preference.
“Specific KRAS mutations show characteristic patterns of tissue preference (Figure 1b,c).”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [32]
KRAS A146 mutations are primarily found in colorectal cancer and are rarely reported in other types.
“KRAS A146 mutations are primarily found in colorectal cancer and are rarely reported in other types.”
From KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance (2024) · cites this paper as [32]
Epidemiological studies connect specific KRAS alleles to clinical outcomes, but the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear.
“Although epidemiological studies connect specific alleles to clinical outcomes, the mechanisms underlying the distinct clinical characteristics of mutant KRAS alleles are unclear.”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [3]
Associations have been uncovered between specific KRAS mutation status and therapeutic responses and clinical outcomes of cancer patients.
“associations have been uncovered between the specific KRAS mutation status and therapeutic responses and clinical outcomes of cancer patients3,6”
From The origins and genetic interactions of KRAS mutations are allele- and tissue-specific (2021) · cites this paper as [3]
The 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 [3]
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 [3]
KRAS is one of the most frequently mutated oncogenes in cancer and is commonly linked to therapeutic resistance and poor prognosis.
“KRAS in particular, is among the most frequently mutated oncogenes in cancer and is commonly associated with therapeutic resistance and poor prognosis1,5,6.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [6]
Mutations in codons 117 (K117N/R) and 146 (A146T/V) are seen exclusively in colon cancers.
“Notably, mutations in codons 117 (K117N/R) and 146 (A146T/V) are seen exclusively in colon cancers [51].”
From Drugging KRAS: Current perspectives and state-of-art review (2022) · cites this paper as [51]
G12D and G12V are the most common KRAS mutations in PDAC, which also shows enrichment for G12R that is rarely found in colorectal and lung cancer.
“G12D and G12V are the most common in PDAC, which also shows enrichment for the G12R mutation that is rarely found in CRC lung and lung cancer (16).”
From KRAS mutation in pancreatic cancer (2021) · cites this paper as [16]
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“Missense substitutions in the KRAS gene, which encodes a monomeric GTPase, activate KRAS protein by inhibiting its ability to hydrolyze GTP or by promoting the rapid exchange of GDP for GTP (Haigis, 2017).”
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- Authors
- Haigis, K. M.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Corresponding author
- Haigis, Kevin M.
- ORCID
- Haigis, Kevin M.
- Venue
- Trends in Cancer
- Publisher
- Elsevier BV
- Published
- 2017-10
- Volume
- 3
- Issue
- 10
- Pages
- 686-697
- ISSN
- 2405-8025 (ISSN-L)
- 2405-8033
- PMC
- PMC5824632
- OpenAlex
- W2754809261
- Cited by
- 373
- References
- 85
- Citations by year
- 2026: 28 · 2025: 45 · 2024: 41 · 2023: 42 · 2022: 60 · 2021: 54 · 2020: 52 · 2019: 39 · 2018: 11 · 2017: 1
- FWCI
- 2.64
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Trends in cancer (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- NIH/NCI (CA178017, CA199252, CA195744)
- 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 › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS, KRAS mutation, oncogenic signaling, downstream signaling pathways, stress response pathways, cancer therapy resistance
- MeSH terms
- Alleles, Animals, Cell Transformation, Neoplastic, Genotype, Humans, Mutation, Neoplasms, Prognosis, Structure-Activity Relationship, Proto-Oncogene Proteins p21(ras), Genetic Predisposition to Disease, GTP Phosphohydrolases, Genetic Association Studies, Molecular Targeted Therapy
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