There is no effective molecularly targeted therapy for T-cell Acute Lymphoblastic Leukemias (T-ALL) and prognosis for relapsed or chemotherapeutic refractory cases remains poor. A large unbiased drug screen performed across cell lines from a broad spectrum of cancers revealed that NOTCH1 mutant T-ALL cells, including lines resistant to gamma-secretase inhibitors are very sensitive to the Bcl-2/xL inhibitor ABT-263. We found that NOTCH1 up regulates the mTOR suppressor REDD1, leading to suppression of the mTOR Complex 1. This in turn results in low MCL-1 levels and ABT-263 sensitivity. Inhibition of NOTCH1 activity in this context leads to robust and sustained up regulation of mTOR signaling which could limit the activity of gamma-secretase inhibitors. Analysis of a small set of patient samples support the findings that NOTCH1 mutant T-ALL have low MCL-1 levels. Most importantly, we show that suppression of mTORC1 by a small molecule inhibitor further sensitizes NOTCH1 mutant T-ALL to ABT-263 resulting in massive apoptosis and in vivo efficacy.

SIGNIFICANCE: This study uncovers a previously unappreciated link between two major oncogenic pathways, the NOTCH and mTOR pathways, with NOTCH1 repressing mTORC1 through REDD1. Further, we show that this suppression results in low MCL-1 levels and that combining mTORC inhibition with BCL-2 inhibition is a promising therapeutic strategy for GSI-resistantNOTCH1-mutant T-ALL.

Citation Format: Anahita Dastur, Anthony Faber, Carlotta Costa, Cyril Benes. Repression of mTORC1 activity in NOTCH1 mutant T-ALL results in sensitivity to the BCL-2 inhibitor ABT-263. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A77.