Vijay V*,
Karisani N*, Shi L, Hung YH, Vu P, Kattel P, Kenney L, Merritt J, Adil R, Wu Q, Zhen Y, Morris R, Kreuzer J, Kathiresan M, Herrera Lopez XI, Ellis H, Gritti I, Lecorgne L, Farag I, Popa A, Shen W, Kato H, Xu Q, Balasooriya ER, Wu MJ, Wan J, Kondo H, Chaturantabut S, Raghavan S, Hall MD, Patnaik S, Shen M, Kelley RK, Cleary JM,
Lawrence MS, Root DE, Patra KC, Silveira VS, Benes CH, Deshpande V, Juric D, Sellers WR, Ferrone CR, Haas W, Vazquez F
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Getz G#, Bardeesy N
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Cancer Discov
(2025)
Abstract
Biliary tract cancers (BTCs) 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 Integrin-a3 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.