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. 2025 Sep 4;15(9):1858-1882.
doi: 10.1158/2159-8290.CD-24-1383.

Generation of a Biliary Tract Cancer Cell Line Atlas Identifies Molecular Subtypes and Therapeutic Targets

Vindhya Vijay #  1   2   3   4 , Negin Karisani #  1   4 , Lei Shi  1   2   3   4 , Yu-Han Hung  1   2   3 , Phuong Vu  1   2   3 , Prabhat Kattel  1   2   3 , Lauren Kenney  1   2   3 , Joshua Merritt  1   2   3 , Ramzi Adil  1   2   3 , Qibiao Wu  1   2   3 , Yuanli Zhen  1   2   3   4 , Robert Morris  1 , Johannes Kreuzer  1 , Meena Kathiresan  1 , Xcanda Ixchel Herrera Lopez  1 , Haley Ellis  1   2   3   4 , Ilaria Gritti  1   2   3   4 , Lilian Lecorgne  1   2   3   4 , Ines Farag  1   2   3   4 , Alexandra Popa  5 , William Shen  1   3 , Hiroyuki Kato  1   2   3   4 , Qin Xu  1   2   3   4 , Eranga R Balasooriya  1   2   3   4 , Meng-Ju Wu  1   2   3   4 , Jinkai Wan  1   2   3   4 , Hiroshi Kondo  1   2   3   4 , Saireudee Chaturantabut  4 , Srivatsan Raghavan  3   4   6 , Matthew D Hall  7 , Samarjit Patnaik  7 , Min Shen  7 , Robin K Kelley  8   9 , James M Cleary  3   7 , Michael S Lawrence  1   2   3 , David E Root  4 , Krushna C Patra  1   10 , Vanessa S Silveira  1   2   3   4 , Cyril H Benes  1 , Vikram Deshpande  1   11 , Dejan Juric  1 , William R Sellers  3   4   6 , Cristina R Ferrone  1 , Wilhelm Haas  1 , Francisca Vazquez  4 , Gad Getz  1   3   4   11 , Nabeel Bardeesy  1   2   3   4
Affiliations

Generation of a Biliary Tract Cancer Cell Line Atlas Identifies Molecular Subtypes and Therapeutic Targets

Vindhya Vijay et al. Cancer Discov. .

Abstract

Biliary tract cancers (BTC) are aggressive malignancies encompassing intrahepatic and extrahepatic cholangiocarcinoma, gallbladder carcinoma, and ampullary carcinoma. Here, we report integrative analysis of 63 BTC cell lines via multi-omics and genome-scale CRISPR screens. We identify widespread EGFR dependency in BTC, alongside dependencies selective to anatomic subtypes. Additionally, we delineate strategies to overcome therapeutic resistance, with combined EGFR inhibition potentiating targeting of KRAS-mutant and FGFR2 fusion-driven models and SHP2 inhibition effective in the latter context. Clustering RNA/protein expression and dependencies data revealed functional relationships transcending single-gene alterations, with biliary, squamous, or dual biliary/hepatocyte lineage signatures stratifying BTC models. These subtypes exhibit distinct dependency profiles-including cell fate transcription factors GRHL2, TP63, and HNF1B, respectively-and demonstrate prognostic significance in patient samples. Potential subtype-specific targetable vulnerabilities include integrinα3 and the detoxification enzyme UXS1. This cell line atlas reveals therapeutic targets in molecularly defined BTCs, unveils disease subtypes, and provides a resource for therapeutic development.

Significance: This integrative analysis of BTC cell lines defines the landscape of vulnerabilities across BTCs, stratifying distinct subtypes, and provides a key resource for studying disease heterogeneity. The findings highlight strategies for targeting BTCs with specific genomic alterations, as well as broader approaches based on shared molecular programs and essential pathways.

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Conflict of interest statement

N.B. reports research grant support from Kinnate Biopharma Inc., Tyra Biosciences, and Servier Laboratories. G.G. receives research funds from IBM, Pharmacyclics/Abbvie, Bayer, Genentech, Calico and Ultima Genomics, and is also an inventor on patent applications filed by the Broad Institute related to MSMuTect, MSMutSig, POLYSOLVER, SignatureAnalyzer-GPU, MSIDetect, and MinumuMM-seq. He is a founder, consultant, and holds privately held equity in Scorpion Therapeutics; he is also a founder of, and holds privately held equity in, PreDICTA Biosciences. F.V. receives research support from the Dependency Map Consortium, Riva Therapeutics, Bristol Myers Squibb, Merck, Illumina, and Deerfield Management. F.V. is on the scientific advisory board of GSK, is a consultant and holds equity in Riva Therapeutics and is a co-founder and holds equity in Jumble Therapeutics. C.H.B. is a current employee and holds privately held equity in Treeline Biosciences. D.E.R. receives research funding from members of the Functional Genomics Consortium (Abbvie, BMS, Jannsen, Merck), and is a director of Addgene, Inc. R.K.K reports research funding to institution from Agios, Astra Zeneca, Bayer, BMS, Compass Therapeutics, Eli Lilly, EMD Serono, Exelixis, Genentech/Roche, Loxo Oncology, Merck, Novartis, Partner Therapeutics, QED, Relay Therapeutics, Servier, Surface Oncology, Taiho, Tyra Biosciences; consulting/advisory fees to self from Compass Therapeutics, Elevar, Exact Sciences, GSK, Kinnate, Moderna, Regeneron, Tyra Therapeutics, J-Pharma Inc; and travel support from AstraZeneca and Merck. J.M.C. receives research funding to his institution from Amgen, Merus, Servier, and Bristol Myers Squibb. He receives research support from Merck, AstraZeneca, Esperas Pharma, Bayer, Tesaro, Arcus Biosciences, and Pyxis; he has also received honoraria for being on the advisory boards of Incyte and Blueprint Medicines and for serving on the data safety monitoring committee for Astrazeneca. He has given educational talks sponsored by Bayer, Bristol Myers Squibb, Merck, AstraZeneca, and Genentech. D.J. reports grants and personal fees from Novartis, Genentech, Syros, and Eisai, grants from Pfizer, Ribon Therapeutics, Infinity, InventisBio, Cyteir, and Arvinas, and personal fees from Relay Therapeutics, Vibliome, Mapkure, and PIC Therapeutics outside the submitted work. SR holds equity in Amgen and receives research support from Microsoft.

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