1. SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.
- Author
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Luk IS, Bridgwater CM, Yu A, Boila LD, Yáñez-Bartolomé M, Lampano AE, Hulahan TS, Boukhali M, Kathiresan M, Macarulla T, Kenerson HL, Yamamoto N, Sokolov D, Engstrom IA, Sullivan LB, Lampe PD, Cooper JA, Yeung RS, Tian TV, Haas W, Saha SK, and Kugel S
- Subjects
- Animals, Humans, Mice, Bile Duct Neoplasms pathology, Bile Duct Neoplasms metabolism, Bile Duct Neoplasms genetics, Bile Duct Neoplasms drug therapy, Cell Adhesion Molecules metabolism, Cell Line, Tumor, Cell Proliferation drug effects, Phosphorylation drug effects, Ribosomal Protein S6 Kinases, 70-kDa metabolism, Signal Transduction drug effects, Guanylate Kinases genetics, Guanylate Kinases metabolism, Protein Phosphatase 2 genetics, Protein Phosphatase 2 metabolism, Adaptor Proteins, Signal Transducing metabolism, Cholangiocarcinoma drug therapy, Cholangiocarcinoma pathology, Cholangiocarcinoma metabolism, Cholangiocarcinoma genetics, Dasatinib pharmacology, Isocitrate Dehydrogenase metabolism, Isocitrate Dehydrogenase genetics, Mutation genetics, src-Family Kinases metabolism, src-Family Kinases antagonists & inhibitors
- Abstract
Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy that frequently exhibits isocitrate dehydrogenase ( IDH1/IDH2 ) 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.
- Published
- 2024
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