RRC ID 79440
Author 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, Kugel S.
Title SRC inhibition enables formation of a growth suppressive MAGI1-PP2A complex in isocitrate dehydrogenase-mutant cholangiocarcinoma.
Journal Sci Transl Med
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.
Volume 16(747)
Pages eadj7685
Published 2024-5-15
DOI 10.1126/scitranslmed.adj7685
PMID 38748774
MeSH Adaptor Proteins, Signal Transducing* / metabolism Animals Bile Duct Neoplasms / drug therapy Bile Duct Neoplasms / genetics Bile Duct Neoplasms / metabolism Bile Duct Neoplasms / pathology Cell Adhesion Molecules / metabolism Cell Line, Tumor Cell Proliferation / drug effects Cholangiocarcinoma* / drug therapy Cholangiocarcinoma* / genetics Cholangiocarcinoma* / metabolism Cholangiocarcinoma* / pathology Dasatinib* / pharmacology Humans Isocitrate Dehydrogenase* / genetics Isocitrate Dehydrogenase* / metabolism Mice Mutation* / genetics Phosphorylation / drug effects Ribosomal Protein S6 Kinases, 70-kDa / metabolism Signal Transduction / drug effects src-Family Kinases* / antagonists & inhibitors src-Family Kinases* / metabolism
Human and Animal Cells RBE(RCB1292) HuCCT1(RCB1960)