KRAS G12C
KRAS G12C refers to a specific oncogenic missense variant of the KRAS gene in which glycine at codon 12 is replaced by cysteine.
KRAS G12C refers to a specific oncogenic missense variant of the KRAS gene in which glycine at codon 12 is replaced by cysteine. This alteration affects the KRAS small GTPase, a central regulator of signaling pathways that control cell proliferation, survival, and differentiation, including downstream MAPK1-related signaling. In cancer biology, KRAS G12C is notable because the introduced cysteine creates a chemically addressable residue that has enabled the development of allele-specific covalent inhibitors, transforming KRAS from a long-considered undruggable target into a clinically actionable one.
Therapeutically, KRAS G12C has become an important target in tumors driven by KRAS-dependent signaling, especially lung adenocarcinoma and colorectal cancer, and it is also being investigated in gastrointestinal tumors and pancreatic cancer models. Current research emphasizes direct KRAS G12C inhibition, combination strategies with EGFR blockade, SOS1 inhibition, and approaches to overcome acquired resistance. Resistance remains a major challenge, with both genetic and non-genetic mechanisms reported in the setting of KRAS inhibition.
Where the papers sit
20 papers from the last 6 months study KRAS G12C directly · updated from PubMed 4 Oct 2026
Study type 0 clinical trials · 1 observational · 7 human data · 10 preclinical · 2 unclassified
Themes 3 themes · 1 paradigm shift
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KRAS-Targeted Lung Cancer Therapy
KRAS-directed treatment in lung cancer is moving beyond single agents toward repurposed drugs, FAK inhibition, and RAF/MEK clamp avutometinib combinations. Novel covalent and noncovalent inhibitors, including CNS-penetrant AM-8719, broaden the search for allele-specific therapy. Amphiregulin-driven EGFR activation recurs as a mechanism of intrinsic and acquired resistance. ctDNA assays and in vivo KRAS degradation point toward earlier molecular monitoring and deeper target suppression.
8 papers · 40%
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KRAS Resistance in Gastrointestinal Cancer
KRAS-directed therapy in gastrointestinal cancer is shifting toward mapping adaptive, genetic, and non-genetic resistance rather than treating response as durable. Colorectal tumors recur through anti-EGFR resistance mutations and other pathway changes, while circulating tumor-cell dynamics during glecirasib may help predict survival and relapse. Farnesylation-driven KRAS phase separation offers a growth mechanism and possible target. Pancreatic studies are extending allele-specific inhibition, but clinical benefit and resistance evolution remain open.
8 papers · 40%
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SOS1 Inhibition and KRAS Resistance
KRAS pathway drug discovery is expanding from direct inhibitors to SOS1 blockade and metabolic vulnerabilities. CNS-penetrant SOS1 inhibitors and agents for KRAS-driven colorectal cancer are being optimized for potency, selectivity, and exposure. MAPK1/DUSP6-linked profiling supports pharmacodynamic assessment, while ATF3-driven asparagine biosynthesis emerges as a route to acquired KRASG12C inhibitor resistance. Proteomic stability and activity assays are being combined to improve target and inhibitor characterization.
4 papers · 20%
Resistance to KRAS G12C inhibition is a plastic adaptive-state problem, not merely a genetic escape problem
The patient-matched colorectal cancer biopsies, organoids, and spatial models studied after combined KRAS G12C and EGFR inhibition showed that subclonal genetic events coexist with transcriptional adaptive states, including inflammatory, mesenchymal, YAP, and fetal-like programs that arise before resistance and can be suppressed through TBK1 targeting 42167227May; the patient-derived xenograft, mouse, and leptomeningeal models of KRAS G12C-mutant non-small cell lung cancer likewise identified tumor-cell-autocrine amphiregulin–EGFR signaling in both intrinsic and acquired resistance, including CNS recurrence, and restored control with EGFR inhibition 42393288Jul; resistant models and a patient-derived model further showed that integrated-stress-response activation drives ATF3–ASNS asparagine reprogramming, with PERK inhibition resensitizing tumors 42270775Jun. Together, these findings replace a resistance account centered on stable genetic escape with one in which reversible signaling, inflammatory, and metabolic cell-state adaptations are independent causes of treatment failure and actionable combination targets.
Papers
The 20 papers from the last 6 months that study KRAS G12C directly, newest first, by theme and by study type. Study types come from PubMed publication types and MeSH headings.
By theme
KRAS-Targeted Lung Cancer Therapy (8)
- FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non-small cell lung cancer. Science translational medicine · 30 Sept 2026 PMID 42814800
- One-pot SP-EXPAR-integrated CRISPR/Cas14a assay for highly specific and versatile detection of ctDNA mutations in lung cancer patients. Analytical methods : advancing methods and applications · 24 Aug 2026 PMID 42635115
- Incidence of KRAS G12C mutations in genitourinary malignancies; emerging target in precision medicine. Oncotarget · 19 Aug 2026 PMID 42615885
- Integrated computational and preclinical evaluation of drug repurposing candidates for KRAS-mutant non-small cell lung cancer. Scientific reports · 13 Aug 2026 PMID 42595781
- Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel, CNS-Penetrant KRAS G12C Inhibitor. Journal of medicinal chemistry · 13 Aug 2026 PMID 42593915
- Amphiregulin-mediated EGFR activation drives both intrinsic and acquired resistance to KRAS G12C inhibitors in KRAS G12C-mutant non-small cell lung cancer. Oncogene · 2 Jul 2026 PMID 42393288
- Identification of Noncovalent Small-Molecules from Virtual Screening Toward the Development of Potential KRAS Inhibitors. Journal of chemical information and modeling · 26 Jun 2026 PMID 42359553
- Targeted KRASG12V Degradation in vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis. Cancer research · 27 May 2026 PMID 42200804
KRAS Resistance in Gastrointestinal Cancer (8)
- The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026. Journal of hematology & oncology · 8 Aug 2026 PMID 42571010
- Signal logic gate mediated by a controllable CRISPR/Cas12a system for simultaneous detection of DNA mutation and methylation. Analytical methods : advancing methods and applications · 16 Jul 2026 PMID 42459132
- Higher frequency of subclonal anti-EGFR resistance mutations in post-treatment samples from patients with colorectal cancer liver metastases following anti-EGFR-based conversion chemotherapy. PloS one · 6 Jul 2026 PMID 42406708
- Forging New Pathways in Oncology: Strategic Insights from the 17th Annual Frontiers in Cancer Science Conference. Cancer research · 2 Jul 2026 PMID 42388021
- The dynamic evolution of circulating tumor cells during glecirasib treatment predicts survival and resistance in gastrointestinal tumors with KRASG12C mutation. Human cell · 1 Jul 2026 PMID 42384131
- The cartography of KRAS inhibitor resistance in colorectal cancer. Cancer cell · 11 Jun 2026 PMID 42276046
- Farnesylation-driven KRAS phase separation promotes colon tumor growth. Cell · 27 May 2026 PMID 42202789
- Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer. Cancer cell · 21 May 2026 PMID 42167227
SOS1 Inhibition and KRAS Resistance (4)
- Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers. Journal of medicinal chemistry · 16 Jun 2026 PMID 42301273
- Stability-Based Proteomic Methods Add Value to Activity-Based Protein Profiling Studies. ACS chemical biology · 11 Jun 2026 PMID 42275002
- Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASG12C inhibitors. Oncogene · 10 Jun 2026 PMID 42270775
- Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer. Journal of medicinal chemistry · 5 Jun 2026 PMID 42247371
By study type
Observational studies and case reports (1)
- Higher frequency of subclonal anti-EGFR resistance mutations in post-treatment samples from patients with colorectal cancer liver metastases following anti-EGFR-based conversion chemotherapy. PloS one · 6 Jul 2026 PMID 42406708
Human data, design not indexed (7)
- One-pot SP-EXPAR-integrated CRISPR/Cas14a assay for highly specific and versatile detection of ctDNA mutations in lung cancer patients. Analytical methods : advancing methods and applications · 24 Aug 2026 PMID 42635115
- Incidence of KRAS G12C mutations in genitourinary malignancies; emerging target in precision medicine. Oncotarget · 19 Aug 2026 PMID 42615885
- The KRAS targeting revolution in metastatic pancreatic cancer: insights from the landmark RASolute-302 trial and emerging allele-specific strategies at ASCO 2026. Journal of hematology & oncology · 8 Aug 2026 PMID 42571010
- Signal logic gate mediated by a controllable CRISPR/Cas12a system for simultaneous detection of DNA mutation and methylation. Analytical methods : advancing methods and applications · 16 Jul 2026 PMID 42459132
- Forging New Pathways in Oncology: Strategic Insights from the 17th Annual Frontiers in Cancer Science Conference. Cancer research · 2 Jul 2026 PMID 42388021
- The dynamic evolution of circulating tumor cells during glecirasib treatment predicts survival and resistance in gastrointestinal tumors with KRASG12C mutation. Human cell · 1 Jul 2026 PMID 42384131
- The cartography of KRAS inhibitor resistance in colorectal cancer. Cancer cell · 11 Jun 2026 PMID 42276046
Preclinical: animal, cell and lab studies (10)
- FAK inhibitor and RAF/MEK clamp avutometinib enhance KRAS G12C inhibitor efficacy in preclinical models of non-small cell lung cancer. Science translational medicine · 30 Sept 2026 PMID 42814800
- Integrated computational and preclinical evaluation of drug repurposing candidates for KRAS-mutant non-small cell lung cancer. Scientific reports · 13 Aug 2026 PMID 42595781
- Property-Biased Covalent DNA-Encoded Library Screening Enabled the Discovery of AM-8719, A Structurally Novel, CNS-Penetrant KRAS G12C Inhibitor. Journal of medicinal chemistry · 13 Aug 2026 PMID 42593915
- Amphiregulin-mediated EGFR activation drives both intrinsic and acquired resistance to KRAS G12C inhibitors in KRAS G12C-mutant non-small cell lung cancer. Oncogene · 2 Jul 2026 PMID 42393288
- Identification of Noncovalent Small-Molecules from Virtual Screening Toward the Development of Potential KRAS Inhibitors. Journal of chemical information and modeling · 26 Jun 2026 PMID 42359553
- Discovery of CNS Penetrant SOS1 Inhibitors for the Treatment of KRAS-Dependent Cancers. Journal of medicinal chemistry · 16 Jun 2026 PMID 42301273
- Stability-Based Proteomic Methods Add Value to Activity-Based Protein Profiling Studies. ACS chemical biology · 11 Jun 2026 PMID 42275002
- Discovery of Highly Potent and Selective SOS1 Inhibitors for the Treatment of KRAS-Driven Colorectal Cancer. Journal of medicinal chemistry · 5 Jun 2026 PMID 42247371
- Farnesylation-driven KRAS phase separation promotes colon tumor growth. Cell · 27 May 2026 PMID 42202789
- Concurrent genetic and non-genetic resistance mechanisms to KRAS inhibition in colorectal cancer. Cancer cell · 21 May 2026 PMID 42167227
Unclassified: not yet indexed with MeSH (2)
- Targeting ATF3-mediated asparagine biosynthesis reverses acquired resistance to KRASG12C inhibitors. Oncogene · 10 Jun 2026 PMID 42270775
- Targeted KRASG12V Degradation in vivo Elicits Lung Adenocarcinoma Regression with Subsequent Relapse from Dysregulated Proteolysis. Cancer research · 27 May 2026 PMID 42200804
Written from 20 PubMed abstracts, each one listed by PMID above. Published: 2026-07-23. Last written: 2026-08-26 by GPT. Drafted by language models from published abstracts; not medical advice.