ArticleClinical cancer research : an official journal of the American Association for Cancer Research2025
Identification of Candidate Alterations Mediating KRASG12C Inhibitor Resistance in Advanced Colorectal and Pancreatic Cancers.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers, 2 of them syntheses that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
9 citing papers in PubMed, 2 syntheses or guidelines pooled it.
- Prognostic significance of KRAS G12C versus non-G12C RAS mutations in metastatic colorectal cancer: a systematic review and meta-analysis.The oncologist · 2026Pooled it
- Research trends and hotspots of circulating tumor DNA in colorectal cancer: a bibliometric study.Frontiers in oncology · 2025Pooled it
- RAS Inhibitors: Changing the Paradigm from the Undruggable.Pharmaceutics · 2026Review
- Abrogation of Oncogenic RAS Signaling by a RAS(ON) Inhibitor Doublet Primes Immune-Refractory KRASG12C-Mutant NSCLC for Immune Checkpoint Blockade.Cancer discovery · 2026Article
- Targeted protein degradation dismantles undruggable targets to reverse immune evasion and therapy resistance in cancer.Frontiers in immunology · 2026Review
- KRAS G12C Inhibition in Solid Tumors: Biological Breakthroughs, Clinical Evidence, and Open Challenges.Cancers · 2025Review
- Adagrasib in the treatment of colorectal cancer.Future oncology (London, England) · 2025Review
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
- FN1 from cancer-associated fibroblasts orchestrates pancreatic cancer metastasis via integrin-PI3K/AKT signaling.Frontiers in oncology · 2025Article
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
purposeKRAS G12C inhibitors can treat KRASG12C-mutant advanced colorectal cancers and pancreatic ductal adenocarcinomas (PDAC), but alterations in Kirsten rat sarcoma (KRAS), EGFR, BRAF, MAP2K1, and other genes bypass KRAS inhibition and reduce therapy efficacy. Our study evaluates the genetic landscape of candidate primary resistance alterations relevant to KRAS targeting in KRASG12C-mutant colorectal cancer and PDAC. EXPERIMENTAL
designWe analyzed two cohorts (national database and Mayo) of patients with advanced colorectal cancer or PDAC tested with next-generation sequencing of ctDNA via Guardant360. Cohorts were divided into three groups: KRASG12C alone (KRASG12C without a resistance gene), KRASG12C with resistance (KRASG12C and ≥1 candidate resistance gene), and KRAS not detected. Candidate resistance mutations were inferred from the reported literature.
resultsAmong the national (13,603 colorectal cancer and 5,016 PDAC cases) and Mayo (741 colorectal cancer and 422 PDAC cases) cohorts, resistance alterations were identified in a considerable number of KRASG12C cases (46.5% of national colorectal cancer, 16.4% of national PDAC, 53.8% of Mayo colorectal cancer, and 36.4% of Mayo PDAC). The presence of resistance alterations was associated with a trend toward worse overall survival in KRASG12C colorectal cancer (P = 0.05).
conclusionsPutative resistance alterations are prevalent in PDAC and colorectal cancer and may limit monotherapy efficacy. Identifying these alterations has potential implications in optimal patient selection for targeted therapies and the development of combination therapy strategies to overcome primary resistance.
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