Abstract 5472: Loss of TSC2 function predicts optimal therapeutic response to combinations of MEK and mTOR inhibitors

Abstract The MAPK-RAS-PI3K signaling network is oncogenic in many human malignancies. The plasticity of cancer cell ‘circuitry’ is an important consideration in the rational design of drug combinations, particularly those targeting this signaling network. Therapies directed at MEK, a downstream RAS effector, have been in various stages of clinical development and shown to exhibit single-agent activity in RAF-mutant tumors. However, there is significant redundancy in the MAPK-PI3K pathway that mediates acute resistance to drugs that target either axis of this network, therefore the optimal use for MEK inhibitors will be in combination. We have previously demonstrated that the combination of MEK and mTOR inhibitors is synergistic in a broad range of tumor cell lines and xenofrafts and mechanistically this is mediated via potent suppression of cap-dependent translation. To better define which cohort of patients would best benefit from this combination modality, we have evaluated the efficacy of MEK and rapalog combinations in TSC2 defective cells. The TSC1/2 complex integrates AKT/mTOR and MAPK circuitry and normally inhibits mTOR via Rheb. However disruption of the TSC complex occurs by mutational inactivation, LOH and inactivating phosphorylation via various kinases, including ERK. Loss of TSC2 function hyperactivates mTOR signaling and confers increased sensitivity to mTOR-directed therapies, including rapalogs. In spite of the known participation of MAPK signaling in TSC function, pharmacological inhibitors of MAPK or other components have not been evaluated in TSC2 null tumors. Cells defective in TSC2 had increased sensitivity to both single agent MEK or rapalog therapies, relative to TSC2 WT cells, and had a much more synergistic interaction that was associated with potent dephosphorylation of the translational repressor, 4E-BP1. Synergy was associated with autophagy induction in TSC2 null cells followed by profound growth arrest that did not respond to growth factor stimulation. Cells with intact TSC2 function did not undergo autophagy after combined MEK and rapalog-inhibitor treatment and did not exhibit the same degree of growth arrest. Bioenergetic profiling indicated that TSC2 null cells had increased levels of oxygen consumption relative to WT cells, indicating changes in metabolic output associated with mTOR activation. In conclusion, these data support the use of combined MEK and rapalog-inhibitor therapy in tumors with defective TSC2 signaling. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5472. doi:10.1158/1538-7445.AM2011-5472