Next batter up! Targeting cancers with KRAS-G12D mutations
Open accessAbstract
KRAS is the most frequently mutated oncogene in cancer. Activating mutations in codon 12, especially G12D, have the highest prevalence across a range of carcinomas and adenocarcinomas. With inhibitors to KRAS-G12D now entering clinical trials, understanding the biology of KRAS-G12D cancers, and identifying biomarkers that predict therapeutic response is crucial. In this Review, we discuss the genomics and biology of KRAS-G12D adenocarcinomas, including histological features, transcriptional landscape, the immune microenvironment, and how these factors influence response to therapy. Moreover, we explore potential therapeutic strategies using novel G12D inhibitors, leveraging knowledge gained from clinical trials using G12C inhibitors.
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KRAS G12D more preferentially interacts with the PI3K/AKT pathway in NSCLC compared to other mutants.
“For example, KRAS G12D more preferentially interacts with the PI3K/AKT pathway in NSCLC compared to other mutants [35].”
From Differential Response and Resistance to KRAS-Targeted Therapy (2025) · cites this paper as [35]
Unlike KRAS G12C, KRAS G12D lacks a reactive residue near the switch-II-binding pocket, making development of covalent inhibitors challenging.
“Unlike the KRAS G12C oncoprotein, which can be successfully inhibited by covalent inhibitors targeting the mutated cysteine residue, 2,3 KRAS G12D lacks a reactive residue near the switch-II-binding pocket, making the development of covalent inhibitors challenging. 1”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [1]
KRAS G12D is the most prevalent KRAS mutant subtype in pancreatic ductal adenocarcinoma and colorectal cancer, and the second most common in lung adenocarcinoma.
“KRAS G12D is the most prevalent KRAS mutant subtype in pancreatic ductal adenocarcinoma (PDAC) and colorectal cancer, and the second most common in lung adenocarcinoma (LUAD). 1”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [1]
KRAS G12D remains undruggable in the clinical setting.
“KRAS G12D remains undruggable in the clinical setting.”
From Anti-tumor efficacy of HRS-4642 and its potential combination with proteasome inhibition in KRAS G12D-mutant cancer (2024) · cites this paper as [1]
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“3 However, recent breakthroughs with KRAS G12C inhibitors (e.g., sotorasib and adagrasib) in combination with epidermal growth factor receptor (EGFR) antibodies have transformed therapeutic strategies for KRAS G12C-mutant CRC. 11 For instance, MRTX1133—a KRAS G12D inhibitor—demonstrates potent anti-tumor effects in pr…”
InfluentialDifferential Response and Resistance to KRAS-Targeted Therapy
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“For example, KRAS G12D more preferentially interacts with the PI3K/AKT pathway in NSCLC compared to other mutants [40].”
- Authors
- Zeissig, M. N., Ashwood, L. M., Kondrashova, O., & Sutherland, K. D.
- Affiliations
- The University of Melbourne (AU)
- The University of Queensland (AU)
- Corresponding author
- Sutherland, Kate D.
- Venue
- Trends in Cancer
- Publisher
- Elsevier BV
- Published
- 2023-11
- Volume
- 9
- Issue
- 11
- Pages
- 955-967
- ISSN
- 2405-8025 (ISSN-L)
- 2405-8033
- OpenAlex
- W4385830709
- Cited by
- 128
- References
- 21
- Citations by year
- 2026: 48 · 2025: 48 · 2024: 28 · 2023: 4
- FWCI
- 3.37
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Trends in cancer (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Victorian Cancer Agency (ECRF22003)
- National Health and Medical Research Council (APP2008631, APP2010275)
- Cure Cancer Australia Foundation (CCAF2023-Zeissig)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Melanoma and MAPK Pathways
- Keywords
- KRAS G12D mutation, KRAS inhibitors, KRAS G12C inhibitors, adenocarcinoma, tumor immune microenvironment, transcriptional landscape, histological features, cancer genomics, targeted cancer therapy
- MeSH terms
- Adenocarcinoma, Humans, Mutation, Proto-Oncogene Proteins p21(ras), Tumor Microenvironment
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