ArticleCancer discovery2022
EGFR Inhibition Potentiates FGFR Inhibitor Therapy and Overcomes Resistance in FGFR2 Fusion-Positive Cholangiocarcinoma.
Article in Cancer discovery, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT06302621 (A Phase Ia/Ib Study of the Combination of the FGFR Inhibitor Pemigatinib and the EGFR Inhibitor Afatinib in Advanced Refractory Solid Tumors), which is not on this map. Cited by 71 papers, 1 of them a synthesis that pooled it.
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.
A Phase Ia/Ib Study of the Combination of the FGFR Inhibitor Pemigatinib and the EGFR Inhibitor Afatinib in Advanced Refractory Solid Tumors
Who cites it
71 citing papers in PubMed, 1 synthesis or guideline pooled it, 94 citations in OpenAlex.
- Criteria for preclinical models of cholangiocarcinoma: scientific and medical relevance.Nature reviews. Gastroenterology & hepatology · 2023Guideline
- FGF/FGFR Alteration Type as a Candidate Enrichment Biomarker for Gunagratinib in Recurrent or Metastatic Head and Neck Cancer: An Exploratory Analysis of Two Early-Phase Trials.Targeted oncology · 2026Trial
- Efficacy and safety of lenvatinib plus gefitinib in lenvatinib-resistant hepatocellular carcinomas: a prospective, single-arm exploratory trial.Signal transduction and targeted therapy · 2024Trial
- Article
- Sequencing of Fibroblast Growth Factor Receptor Inhibitors in Cholangiocarcinoma: A Review of Published Cases.JCO precision oncology · 2026Review
- Co-repression of Yap1 and Sox9 abrogates established cholangiocarcinoma by eliminating transcriptional compensation.Clinical and molecular hepatology · 2026Article
- Integrative multi-omics and single-cell analysis identifies EGFR pathway activation and metabolic reprogramming as potential synthetic lethal vulnerabilities in resistance to the FGFR inhibitor AZD4547.Journal of translational medicine · 2026Article
- How to efficiently establish animal models of cholangiocarcinoma: challenges and inspiration.Medical review (2021) · 2026Review
- Article
- Preclinical mouse models for studying cholangiocarcinoma.Liver research (Beijing, China) · 2026Review
- FGFR2-Rearranged Biliary Tract Cancer: Biology, Resistance Mechanisms, and Emerging Therapeutic Strategies.Cancers · 2026Review
- Co-repression ofbioRxiv : the preprint server for biology · 2026Article
- Integrative Sequencing and Proteogenomic Approaches to Intratumoral Heterogeneity in Cholangiocarcinoma: Implications for Precision Diagnosis and Therapy.Medical sciences (Basel, Switzerland) · 2026Review
- Fusion oncoproteins orchestrate tumorigenesis and sustain malignant progression via a positive feedback mechanism.Cell & bioscience · 2026Review
- Saturation mutagenesis identifies activating and resistance-inducing FGFR kinase domain mutations.Nature genetics · 2026Article
- Fibroblast Growth Factor Receptor (FGFR) Inhibitors for the Treatment of Cholangiocarcinoma: Key Therapeutic Developments and Knowledge Gaps.Drug design, development and therapy · 2026Review
- mTOR signaling in cholangiocarcinoma: mechanistic insights and therapeutic opportunities.Frontiers in pharmacology · 2026Review
- Cholangiocarcinoma 2026: status quo, unmet needs and priorities.Nature reviews. Gastroenterology & hepatology · 2026Review
- Clonorchis sinensis and cholangiocarcinoma: molecular mechanisms and biomarker advances.Parasite (Paris, France) · 2026Review
- The role of ADAM8 in intrahepatic cholangiocarcinoma.Discover oncology · 2025Review
11 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
23 authors at 4 institutions in 2 countries.
Funding
Abstract
FGFR inhibitors are approved for the treatment of advanced cholangiocarcinoma harboring FGFR2 fusions. However, the response rate is moderate, and resistance emerges rapidly due to acquired secondary FGFR2 mutations or due to other less-defined mechanisms. Here, we conducted high-throughput combination drug screens, biochemical analysis, and therapeutic studies using patient-derived models of FGFR2 fusion-positive cholangiocarcinoma to gain insight into these clinical profiles and uncover improved treatment strategies. We found that feedback activation of EGFR signaling limits FGFR inhibitor efficacy, restricting cell death induction in sensitive models and causing resistance in insensitive models lacking secondary FGFR2 mutations. Inhibition of wild-type EGFR potentiated responses to FGFR inhibitors in both contexts, durably suppressing MEK/ERK and mTOR signaling, increasing apoptosis, and causing marked tumor regressions in vivo. Our findings reveal EGFR-dependent adaptive signaling as an important mechanism limiting FGFR inhibitor efficacy and driving resistance and support clinical testing of FGFR/EGFR inhibitor therapy for FGFR2 fusion-positive cholangiocarcinoma. SIGNIFICANCE: We demonstrate that feedback activation of EGFR signaling limits the effectiveness of FGFR inhibitor therapy and drives adaptive resistance in patient-derived models of FGFR2 fusion-positive cholangiocarcinoma. These studies support the potential of combination treatment with FGFR and EGFR inhibitors as an improved treatment for patients with FGFR2-driven cholangiocarcinoma. This article is highlighted in the In This Issue feature, p. 1171.
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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.