Iris S Luk, Caroline M Bridgwater, Angela Yu, Liberalis D Boila, Mariana Yáñez-Bartolomé, Aaron E Lampano, Taylor S Hulahan, Myriam Boukhali, Meena Kathiresan, Teresa Macarulla, Heidi L Kenerson, Naomi Yamamoto, David Sokolov, Ian A Engstrom, Lucas B Sullivan, Paul D Lampe, Jonathan A Cooper, Raymond S Yeung, Tian V Tian, Wilhelm Haas, Supriya K Saha, Sita Kugel
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...
May 15, 2024: Science Translational Medicine