Abstract A015: A synergistic combination of a novel mTORC1-activator with proteasome inhibitor confers a remission in acute myeloid leukemia

Abstract Despite the well-characterized oncogenic properties of mTORC1, in the presence of chemotherapy or other stress conditions, the suppression of mTORC1 promotes survival and bestows tumors with drug resistance. While highly potent inhibitors of mTORC1 were developed, small molecules that activate mTORC1 directly are lacking. The best way to activate mTORC1 is by suppressing its negative regulator, the tuberous sclerosis complex, which comprises TSC1, TSC2, and TBC1D7. We discovered that, deleting TSC2 upsurged the sensitivity of multiple myeloma cells to proteasome inhibitors (PI s). To replicate this pharmacologically, we designed in silico docking and additional chemical modifications to create AcTor, a potential first-of-its-kind TSC2 inhibitor. When AcTor was used in combination with the proteasome inhibitor ixazomib (IXZ), we identified a significant boost in cytotoxic activity in multiple myeloma cells. The combination had an even stronger effect in various acute myeloid leukemia (AML) cell lines. AcTor and IXZ together led to a rapid loss of mitochondrial activity in AML cells, specifically affecting complex IV of the electron transport chain and generating ROS. In animal models, AcTor alone accelerated AML growth, which aligns with mTORC1 activation. However, when combined with IXZ for three weeks, the growth of AML was inhibited, and the leukemic cells underwent apoptosis. This effect was perceived in both peripheral blast cells and the leukemic stem cells in the bone marrow, which are particularly challenging to eliminate. In a relapse model of AML, the AcTor/IXZ treatment sustained to be effective even after the tumor reoccurred. We suggest that treatment courses with AcTor and IXZ could offer a lasting anti-AML benefit, both before and after relapse. Citation Format: Shakti Prasad Pattanayak, Priyashree Sunita, Omid Hajihassani, Kelsey Fisher-Wellman, David Wald, Leif A Eriksson, Boaz Tirosh. A synergistic combination of a novel mTORC1-activator with proteasome inhibitor confers a remission in acute myeloid leukemia [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy; 2024 Oct 18-21; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2024;12(10 Suppl):Abstract nr A015.