Abstract 3846: Sensitivity of NOTCH1 mutant T-ALL to ABT-263

Effective targeted therapies are lacking for refractory and relapsed T-cell Acute Lymphoblastic Leukemia (T-ALL). Analysis of a large cell line screen revealed that NOTCH1 mutant T-ALL cells are sensitive to the Bcl-2/xL inhibitor ABT-263. We show that NOTCH1 inhibits the mTOR complex 1, resulting in low MCL-1 levels and sensitization to ABT-263. Further suppression of mTORC1 using small molecule inhibitors in combination with ABT-263 results in very high levels of apoptosis and tumor regressions in vivo. This suggests new therapeutic opportunities for NOTCH1 mutant T-ALL, including in the setting of gamma-secretase inhibitor (GSI) resistance. Citation Format: Anahita Dastur, Carlotta Costa, Anthony Faber, Cyril Benes. Sensitivity of NOTCH1 mutant T-ALL to ABT-263. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3846.