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Updated: Mar 6, 2026
Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
Published on: September 20, 2016
Gatekeeper Mutations and Intratumoral Heterogeneity in FGFR2-Translocated Cholangiocarcinoma
Elizabeth C Smyth1, Irina S Babina2, Nicholas C Turner3,4
1Department of Gastrointestinal Oncology, Royal Marsden Hospital, London, United Kingdom.
Abstract:
FGFR2 genetic translocations are frequent in cholangiocarcinoma, yet despite initial sensitivity to FGFR inhibitors in clinic, patients quickly become resistant to targeted therapies. The work published by Goyal and colleagues demonstrates that acquisition of gatekeeper mutations in FGFR2 and intratumoral heterogeneity drive resistance in patients with FGFR2-translocated intrahepatic cholangiocarcinoma, which will have important implications for management of the disease in clinic. Cancer Discov; 7(3); 248-9. ©2017 AACR.See related article by Goyal et al., p. 252.
Insights
FGFR2 genetic translocations drive cholangiocarcinoma. Gatekeeper mutations and tumor heterogeneity cause resistance to targeted therapies, impacting clinical management.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Fibroblast growth factor receptor 2 (FGFR2) genetic translocations are common in intrahepatic cholangiocarcinoma.
- Patients initially respond to FGFR inhibitors, but resistance rapidly develops.
Purpose of the Study:
- To investigate the mechanisms of acquired resistance to FGFR inhibitors in FGFR2-translocated cholangiocarcinoma.
Main Methods:
- Analysis of patient tumor samples.
- Genetic sequencing to identify mutations.
- Assessment of intratumoral heterogeneity.
Main Results:
- Acquisition of gatekeeper mutations in FGFR2 was identified as a key driver of resistance.
- Intratumoral heterogeneity contributes to therapeutic resistance.
- These factors explain the rapid development of resistance in patients.
Conclusions:
- Understanding these resistance mechanisms is crucial for improving treatment strategies.
- Targeted therapies need to account for gatekeeper mutations and tumor heterogeneity.
- This research has significant implications for the clinical management of cholangiocarcinoma.
