ArticleNPJ precision oncology2025
Mechanisms of KRAS inhibitor resistance in KRAS-mutant colorectal cancer harboring Her2 amplification and aberrant KRAS localization.
Article in NPJ precision oncology, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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The trial behind it
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Who cites it
10 citing papers in PubMed.
- Targeted therapeutic strategies forTranslational lung cancer research · 2026Review
- RAS Inhibitors: Changing the Paradigm from the Undruggable.Pharmaceutics · 2026Review
- Pancreatic ductal adenocarcinoma: integrating molecular insights for targeted interventions.Signal transduction and targeted therapy · 2026Review
- Advances in targeting KRAS mutations: A promising approach for the treatment of non‑small cell lung cancer (Review).Oncology reports · 2026Review
- Transforming Gastric Biopsy Diagnostics: Integrating Omics Technologies and Artificial Intelligence.Biomedicines · 2026Article
- Targeting CAD with a tumor microenvironment-responsive nano-heterojunction for synergistic induction of cuproptosis and inhibition of colorectal cancer progression.Journal of nanobiotechnology · 2025Article
- Review
- Recent Advances in Anti-Cancer Drugs.International journal of molecular sciences · 2025Article
- Response and Resistance to RAS Inhibition in Cancer.Cancer discovery · 2025Review
- Applications and advances of multi-omics technologies in gastrointestinal tumors.Frontiers in medicine · 2025Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
KRAS-specific inhibitors have shown promising antitumor effects, especially in non-small cell lung cancer, but limited efficacy in colorectal cancer (CRC) patients. Recent studies have shown that EGFR-mediated adaptive feedback mediates primary resistance to KRAS inhibitors, but the other resistance mechanisms have not been identified. In this study, we investigated intrinsic resistance mechanisms to KRAS inhibitors using patient-derived CRC cells (CRC-PDCs). We found that KRAS-mutated CRC-PDCs can be divided into at least an EGFR pathway-activated group and a PI3K/AKT pathway-activated group. In the latter group, PDCs with PIK3CA major mutation showed high sensitivity to PI3K+mTOR co-inhibition, and a PDC with Her2 amplification with PIK3CA minor mutation showed PI3K-AKT pathway dependency but lost KRAS-MAPK dependency by cytoplasmic localization of KRAS. In the PDC, Her2 knockout restored KRAS plasma membrane localization and KRAS inhibitor sensitivity. The current study provides insight into the mechanisms of primary resistance to KRAS inhibitors, including aberrant KRAS localization.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.