Abstract 1555: Use of a mouse model of constitutive mTOR inhibition to identify molecular modulators of acquired resistance.

Abstract The AKT/PI3K/mTOR signaling pathway is hyperactivated in cancers, including both solid tumors and hematologic malignancies. This hyperactivation is often due to an overexpression or mutation in PI3K, which is upstream of AKT, or a down regulation of PTEN, an inhibitor of the PI3K pathway. mTOR is a central downstream target of this pathway and is a critical modulator of cell cycle, size, proliferation and metabolism. Resistance to mTOR inhibition has been reported in many tumors as well as in certain cell lines, resulting in decreased efficacy of cancer therapy involving this class of inhibitor. In these studies, mice (Mtortm1.1Lgm) with constitutive reduction in mTOR protein level were crossed to mice (Lck-MyrAkt2) that spontaneously develop thymic lymphomas due to constitutive AKT activation to simulate mTOR inhibitor treatment of thymic lymphoma development. The Lck-MyrAkt2 mice spontaneously develop thymic lymphomas at 10-20 weeks of age, and frequently harbor a 14;15 translocation that leads to the apposition of the TCRalpha and Myc genes. Tumor formation was significantly delayed in the mTOR knockdown x Lck-MyrAkt2 cohort, and the mice had a median survival of 181 days compared to 88 days in mice with normal mTOR expression. A similar t(14;15) translocation frequency was observed in thymic lymphomas of mice from both groups. To evaluate potential mTOR resistance mechanisms, gene expression profiling (GEP) of tumors arising from both groups of mice was performed. Molecular and functional enrichment analysis of the genes differentially expressed in the tumors arising despite mTOR inhibition was performed. Increased expression of an oncogenic transcription factor was observed, and is the subject of on-going investigation. Citation Format: Joy Gary, Jinfei Xu, John Simmons, Alexander Kovalchuk, Wendy Dubois, Joseph Testa, Beverly Mock. Use of a mouse model of constitutive mTOR inhibition to identify molecular modulators of acquired resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1555. doi:10.1158/1538-7445.AM2013-1555