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Published on: December 26, 2016
Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets
David K Lau1, Dmitri Mouradov2, Wiphawan Wasenang3
1Olivia Newton John Cancer Research Institute, Austin Health, Level 5 ONJ Centre, 145 Studley Road, Heidelberg, Melbourne, VIC 3084, Australia; School of Cancer Medicine, La Trobe University, Melbourne, VIC 3084, Australia.
Abstract:
Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers.
Insights
Biliary tract cancer (BTC) cell lines serve as accurate models for primary tumors, revealing distinct molecular subtypes and potential therapeutic targets. These models identified vulnerabilities in MAPK signaling and ERBB2/FGFR pathways for targeted therapies.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Biliary tract cancers (BTCs) lack approved targeted therapies.
- Genomic profiling of primary BTCs suggests potential drug targets but requires validated models for evaluation.
Purpose of the Study:
- To characterize 22 BTC cell lines for their utility as models of primary BTC.
- To identify molecular subtypes and vulnerabilities within BTC.
Main Methods:
- Genomic and transcriptomic profiling of 22 BTC cell lines.
- Comparison of cell line molecular profiles with primary tumors and patient-derived organoids.
- Interrogation of MAPK signaling pathways and drug sensitivity.
Main Results:
- BTC cell lines accurately recapitulate the genomic and transcriptomic features of primary tumors.
- Two major transcriptomic subtypes (epithelial and mesenchymal) were identified, consistent in cell lines, organoids, and tumors.
- Mechanisms of MAPK signaling activation, including BRAF/MEK mutations with RTK overexpression, were revealed.
- Cell lines with ERBB2 or FGFR alterations showed sensitivity to targeted agents.
- IDH1-mutant cell lines were unexpectedly unresponsive to IDH1 inhibitors in vitro.
Conclusions:
- BTC cell lines are validated as robust preclinical models for studying biliary tract cancers.
- Specific molecular subtypes and vulnerabilities, particularly in MAPK signaling, were identified.
- The study highlights potential targeted therapies for ERBB2/FGFR-altered BTCs and questions IDH1 inhibitor efficacy in certain contexts.
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