Abstract A163: A diverse array of mutations in MTOR are hyperactivating and correlate with rapamycin sensitivity.

Abstract

Abstract Components of the PI3K-Akt-mTOR signaling axis are frequently mutated in cancer but relatively few mutations have been observed in the MTOR gene itself, which encodes the mTOR kinase. We used cancer genome sequencing data to generate a catalogue of over 450 MTOR point mutations found in cancer and from these identified a set of over 25 that cause mTOR pathway hyperactivation in cells. Mutations occur in multiple cancer types and cluster in several distinct regions in the C-terminal half of mTOR. The distribution and diversity of hyperactivating mutations is distinct from those found in kinases such as AKT1 or BRAF but similar to the pattern seen in PIK3CA. The mutations do not affect the sub-cellular localization of mTOR or its capacity to nucleate the mTORC1 and mTORC2 complexes, but the mutants do bind less DEPTOR, an mTOR inhibitor. In kinetic analyses, several of the most frequently recurrent mutations demonstrate increased K-cat over wild-type mTOR, suggesting that these mutations alter the mTOR kinase itself. Lastly, cancer cell lines with naturally arising mTOR mutations that fall within the clusters exhibited hypersensitivity to mTOR inhibitors. Thus, a diverse set of mutations in mTOR can activate the mTOR pathway and may predict which patients are most likely to respond to rapamycin-based therapies. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A163. Citation Format: Brian Grabiner, David Sabatini. A diverse array of mutations in MTOR are hyperactivating and correlate with rapamycin sensitivity. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A163.