SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma

• Published in: Science translational medicine 2024-05, Vol.16 (747), p.eadj7685-eadj7685
• Main Authors: Luk, Iris S, Bridgwater, Caroline M, Yu, Angela, Boila, Liberalis D, Yáñez-Bartolomé, Mariana, Lampano, Aaron E, Hulahan, Taylor S, Boukhali, Myriam, Kathiresan, Meena, Macarulla, Teresa, Kenerson, Heidi L, Yamamoto, Naomi, Sokolov, David, Engstrom, Ian A, Sullivan, Lucas B, Lampe, Paul D, Cooper, Jonathan A, Yeung, Raymond S, Tian, Tian V, Haas, Wilhelm, Saha, Supriya K, Kugel, Sita
• Format: Article
• Language: English
• Subjects: Adaptor Proteins, Signal Transducing - metabolism; AKT protein; Animals; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - metabolism; Bile Duct Neoplasms - pathology; Bile ducts; Cell Adhesion Molecules - metabolism; Cell culture; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Cell size; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; Cholangiocarcinoma - metabolism; Cholangiocarcinoma - pathology; Dasatinib - pharmacology; Dehydrogenases; Guanylate kinase; Guanylate Kinases - genetics; Guanylate Kinases - metabolism; Humans; Isocitrate dehydrogenase; Isocitrate Dehydrogenase - genetics; Isocitrate Dehydrogenase - metabolism; Kinases; Malignancy; Mice; Molecular modelling; Mutants; Mutation - genetics; Organoids; p70 S6 kinase; Phosphoprotein phosphatase; Phosphorylation; Phosphorylation - drug effects; Protein biosynthesis; Protein phosphatase; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Proteins; Ribosomal protein S6; Ribosomal Protein S6 Kinases, 70-kDa - metabolism; Signal Transduction - drug effects; Src protein; src-Family Kinases - antagonists & inhibitors; src-Family Kinases - metabolism; TOR protein
• ISSN: 1946-6234; 1946-6242; 1946-6242; 1946-3242
• DOI: 10.1126/scitranslmed.adj7685

Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase ( ) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and is hypersensitive to inhibition by dasatinib, but the molecular mechanism underlying this sensitivity is unclear. We found that dasatinib reduced p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to substantial reductions in cell size and de novo protein synthesis. Using an unbiased phosphoproteomic screen, we identified membrane-associated guanylate kinase, WW, and PDZ domain containing 1 (MAGI1) as an SRC substrate in IDHm ICC. Biochemical and functional assays further showed that SRC inhibits a latent tumor-suppressing function of the MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6 signaling in IDHm ICC. Inhibiting SRC led to activation and increased access of PP2A to dephosphorylate S6K, resulting in cell death. Evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to dasatinib is due to increased phospho-S6 (pS6). To block pS6, we paired dasatinib with the S6K/AKT inhibitor M2698, which led to a marked reduction in pS6 in IDHm ICC cell lines and patient-derived organoids in vitro and substantial growth inhibition in ICC patient-derived xenografts in vivo. Together, these results elucidated the mechanism of action of dasatinib in IDHm ICC, revealed a signaling complex regulating S6K phosphorylation independent of mTOR, suggested markers for dasatinib sensitivity, and described a combination therapy for IDHm ICC that may be actionable in the clinic.