Abstract 3984: Combination S6K and TAM tyrosine kinase targeting in PTEN-deficient glioma

Loss of PTEN is one of the most frequent driver events in primary glioblastoma, conferring the ability to reconfigure metabolism and enhance apoptosis resistance to transformed glial cells. The ribosomal S6 protein kinases (S6Ks) are hyperactivated in PTEN-deficient settings, and genetic inactivation studies have shown that S6K1 deficiency can reduce the oncogenic growth of PTEN-deficient neoplasia. Investigating pharmacologic agents, we found that the S6K inhibitor LY-2584702 selectively elicits cytotoxic responses in PTEN-deficient cells when combined with the TAM kinase inactivating agent BMS-777607. Combined knockdown of TAM kinases sensitized cells to single agent treatment with LY-2584702. Conversely, expression of activated S6K1 or elevated AXL protected from combination treatment. These results indicate that both the TAMS and S6K1 are key regulators of survival in PTEN deficient cells. Citation Format: Kelli N. Ennis, Pranjal Sarma, Catherine A. Behrmann, Jie Wang, David R. Plas. Combination S6K and TAM tyrosine kinase targeting in PTEN-deficient glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3984.