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Targeted therapies in biliary tract cancer-when precision becomes imprecise
C J O'Rourke1, J V Schou2, J B Andersen1
1Biotech Research and Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen.
ESMO Gastrointestinal Oncology
|February 6, 2026
Summary
Targeted therapies offer benefits for advanced biliary tract cancers (BTCs) with specific alterations. However, resistance mechanisms limit patient response, necessitating refined molecular criteria for better treatment selection and combination therapies.
Area of Science:
- Oncology
- Gastroenterology
- Molecular Biology
Background:
- Advanced biliary tract cancers (BTCs) show promise for targeted therapies due to actionable genetic alterations.
- Fibroblast growth factor receptor (FGFR) inhibitors and isocitrate dehydrogenase 1 (IDH1) inhibitors are approved for specific BTC subtypes.
- A subset of patients does not respond to targeted therapies, even with molecularly matched criteria, indicating unmet needs.
Purpose of the Study:
- To investigate the molecular mechanisms underlying resistance to targeted therapies in advanced BTCs.
- To identify novel biomarkers and refine patient selection criteria for targeted treatments.
- To explore strategies for overcoming therapeutic resistance and improving patient outcomes.
Main Methods:
- Analysis of genetic (DNA) and non-genetic (transcriptional, translational, post-translational) alterations in signaling networks.
- Identification of co-occurring resistance biomarkers in BTC tumors.
- Correlation of molecular profiles with therapeutic response and resistance patterns.
Main Results:
- BTCs exhibit oncogenic addiction to signaling networks, not just individual genes, contributing to resistance.
- Primary resistance is mediated by alterations in pathways upstream, downstream, or parallel to the targeted alteration.
- Limited duration of response suggests complex resistance mechanisms beyond the primary target.
Conclusions:
- Refining molecular criteria to include resistance biomarkers is crucial for patient selection.
- Understanding resistance mechanisms will enable the development of next-generation combination therapies.
- Improved patient stratification and combination strategies can maximize treatment benefits and prolong response duration in BTCs.
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