ArticleCancer cell2026
Paneth-like transition drives resistance to dual targeting of KRAS and EGFR in colorectal cancer.
Article in Cancer cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
- Mutant KRAS-mAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Oral KRAS G12D inhibitor GFH375 for previously treated advanced solid tumors with KRASNature medicine · 2026Article
- High-Content CRISPR Screening: Methods and Applications.MedComm · 2026Review
- Prognostic value of genes associated with metastasis and propionate metabolism in rectal cancer.Journal of gastrointestinal oncology · 2026Article
- KRAS in Colorectal Cancer: Tumorigenesis, Surgical Implications and Evolving Treatment Target.Current oncology (Toronto, Ont.) · 2026Review
- Epithelial-mesenchymal transition in carcinoma: navigating phenotypic states to target resistance and metastasis.Cancer metastasis reviews · 2026Review
- Article
- MetaScreener: a robust dual-mode framework for directional prioritization of actionable signatures through multi-dataset and multi-approach integration.Journal of translational medicine · 2026Article
- Cisplatin resistance in oral squamous cell carcinoma: mechanisms, reversal strategies, and emerging technologies.Frontiers in physiology · 2026Review
Corrections and comments
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Authors and funding
28 authors.
Funding
Abstract
While dual KRAS and epidermal growth factor receptor (EGFR) inhibition shows promise in treating KRAS-mutant colorectal cancer (CRC), resistance remains a major challenge. Using genetically engineered mouse models, patient-derived organoids and xenografts, as well as clinical specimens, we discover that colorectal tumors surviving combined KRAS and EGFR inhibition acquire a Paneth-like cell state-a secretory lineage typically confined to the intestinal crypt. Lineage tracing reveals that CRC cells evade dual therapy by transitioning into a Paneth-like state. Through integrated transcriptomic analysis and CRISPR genetic screening, we identify SMAD1 as a key regulator of this lineage plasticity, promoting resistance by directly activating FGFR3. Genetic or pharmacological inhibition of FGFR3 prevents the Paneth-like transition, restores drug sensitivity, and synergizes with KRAS-EGFR inhibition across multiple preclinical models. These findings reveal that the SMAD1-FGFR3 axis triggers Paneth-like plasticity to drive KRAS-EGFR dual therapy resistance in CRC and highlight FGFR3 blockade as a promising strategy to overcome plasticity-driven drug tolerance.
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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.