A COMBINATION STRATEGY TO COUNTERACT PTEN-DEFICIENCY BY TARGETING THE S6 AND TAM KINASES IN GLIOBLASTOMA

PTEN deficiency affects the majority of glioblastomas, triggering signal transduction pathways that induce anabolic metabolism and apoptosis resistance. The mTOR complex 1 (mTORC1) and S6 kinases (S6Ks) are key mediators of metabolic reprogramming and apoptosis resistance in PTEN-deficient cells. S6K1 can be inhibited using LY2584702, a selective inhibitor that has been tested in Phase 1 clinical trials. We show here that LY2584702 can be used in combination with the TAM tyrosine kinase inhibitor BMS777607 to interfere with anabolic metabolism and restore cell death pathways in PTEN-deficient glioblastoma cells. In vivo, combination treatment reduced the growth rate of PTEN-deficient glioblastoma cells in both subcutaneous and orthotopic tumor settings. The data indicate that the TAM kinases, consisting of the tyrosine kinases TYRO3, AXL, and MERTK, can be targeted together with the S6Ks to counteract PTEN-deficiency in glioblastoma.