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SRC Inhibition Enables Formation of a Growth Suppressive MAGl1-PP2A Complex in Isocitrate Dehydrogenase Mutant Cholangiocarcinoma
Sita Kugel1, Iris S. Luk1, Caroline M. Bridgwater1*, Angela Yu1, Liberalis D. Boila1, Aaron E. Lampano1, Taylor S.
Hulahan1, Myriam Boukhali3, Meena Kathiresan3, Heidi L. Kenerson4, David Sokolov1, Ian A. Engstrom1, Lucas B. Sullivan1,
Paul D. Lampe1, Jonathan A. Cooper2, Raymond S. Yeung4, Wilhelm Haas3, Supriya K. Saha1
1Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
2Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
3The Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts 02114, USA
4University of Washington Department of Surgery, Seattle, WA 98195, USA
Intrahepatic cholangiocarcinoma (ICC) is an aggressive bile duct malignancy exhibiting frequent isocitrate dehydrogenase
(IDH1/IDH2) mutations. Mutant IDH (IDHm) ICC is dependent on SRC kinase for growth and survival and hypersensitive to
inhibition by dasatinib, but the molecular mechanism behind this sensitivity is unclear. We found that dasatinib reduced
p70 S6 kinase (S6K) and ribosomal protein S6 (S6), leading to significant 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 a novel SRC substrate in IDHm ICC. Biochemical and functional assays further showed
that SRC relieves a latent tumor suppressing function of MAGI1-protein phosphatase 2A (PP2A) complex to activate S6K/S6
signaling in IDHm ICC. Inhibiting SRC leads to activation and increased access of PP2A to dephosphorylate S6K and cell
death. Finally, evidence from patient tissue and cell line models revealed that both intrinsic and extrinsic resistance to
dasatinib is due to increased phospho-S6 (pS6) levels. To block pS6, we paired dasatinib with an S6K inhibitor. The
combination led to dramatic reduction in pS6 in IDHm ICC cell lines and patient derived organoids. Taken together, these
results explain the mechanism of action of dasatinib in IDHm ICC, reveal a novel signaling complex regulating S6K
phosphorylation independent of mTOR, identify biomarkers for dasatinib sensitivity and describe a novel combination
therapy that is immediately actionable in the clinic.
Funding: This work was supported in part by National Institutes of Health grants 5R37CA241472 and 1R01CA255015 to
S.K, 5R21CA231486 and 5K08CA194268 to S.S. Evening for Maria Fund to S.S. and Cholangiocarcinoma Foundation
Postdoctoral Fellowship to I.L.
Speakers
Sita Kugel