Glioblastoma (GB) is the most common malignant primary brain tumor, which is characterized by marked intra-tumor genetic heterogeneity in receptor tyrosine kinases (RTK) genes. Aberrations in the RTK/PI3K/Akt pathways in GB leads to an abnormal signaling pathway of mechanistic target of Rapamycin (mTOR). mTOR exists in two distinct complexes, namely, mTORC1 and mTORC2, which are involved in regulation of cell survival, growth, and motility. In this investigation, we test the hypothesis that the genetic heterogeneity of GBM cells and its stem cells with respect to the expression of EGFR and/or PDGFRα may define the treatment efficacy of RTK inhibitors with or without PI3K/ mTOR inhibitors. We demonstrated that GB tumors over-expressed PDGFRα and EGFR at range of 80% and 30%, respectively, with varying degree of overlap. Combined treatment with the inhibitors of PDGFRα (AC 710) or EGFR (gefitinib), with or without inhibitors of mTORC1 (rapamycin) or mTORC1/2 (Torin1 and Torin 2), led to suppression of cell proliferation, cell cycle, cell migration and drug resistance in GB cells to varying degrees that correlated with EGFR or PDGFRα expression. Downstream signaling pathway substrates of mTORC 1 and 2, namely pS6k and pAkt, respectively, were suppressed by combined treatments of RTK and mTORC1/2 inhibitors. Furthermore, GB stem cell self-renewal and growth was also suppressed with combined treatments. The combination of AC710 plus mTORC1/2 inhibitor, Torin2, was the most effective. These findings underscore the usefulness of determining PDGFRα and EGFR status when considering viable PI3K/mTOR inhibitors for targeted treatment of GB.
Citation Format: Anubhav G. Amin, Arthur Wang, Alex Braun, Michael Tobias, Raj Murali, Meena Jhanwar-Uniyal. Therapeutic implications of mTORC1 and mTORC2 inhibitors in genetically heterogeneous glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3125. doi:10.1158/1538-7445.AM2017-3125