Abstract 6509: GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors

Abstract

Abstract Mammalian target of rapamycin (mTOR), a serine/threonine kinase, is the central signal molecule in regulating cell growth, metabolism, angiogenesis, and survival. The first generation of mTOR inhibitors specifically inhibit mTORC1 but are insensitive to mTORC2 and cannot eliminate the downstream signaling cascade in cancer. GT0486, a second-generation mTORC1/2 dual inhibitor, can selectively suppress mTOR kinase activity while has no inhibitory effect on other kinase receptors. We investigate the anti-tumor efficacy of GT0486 in a variety of tumor cells and xenograft animal models in vitro and in vivo. The combination effects of GT0486 and BTKi (BTK inhibitor) were also evaluated. Compared with other mTOR inhibitors (GDC-0349, AZD-2014, Rapamycin, GDC-0941, and CC-223), GT0486 exhibits the stronger inhibitory activity on human tumor cells, such as U87(glioma), PC-3(prostate cancer), MDA-MB-468(breast cancer) and Huh-7(liver cancer). In B-cell lymphoma, compared with the CC-223, GT0486 shows greater inhibitory potency against TMD8, DoHH2 and WSU-DLCL2, with IC50 values of 85nM, 96nM and 83nM, respectively. Moreover, in the U87 and the PC-3 xenograft animal models, GT0486 strongly reduced tumor growth in dose dependent manner. High synergistic effects were observed with GT0486 in combination with BTK inhibitors, including Acalabrutinib, Ibrutinib, Zanubrutinib and Orelabrutinib in the BTKi sensitive TMD8 cells. In BTKi resistant DoHH2 cells, GT0486 also enhanced the drug sensitivity of BTKi. The possible biomarkers on the synergistic mechanism were further studied. GT0486 improves the role of BTKi on cell cycle arrest in phase G1. At the same time, the phosphorylation levels of mTOR downstream effectors AKT, 4EBP1 and S6 were dose-dependently downregulated after GT0486 treatment, and a significant reduction were observed when combined with BTKi. These results demonstrate that GT0486 is a promising dual mTOR1/2 inhibitor, which is currently undergoing clinical phase I study in China for the treatment of solid tumors. Strong synergistic effects observed with GT0486 in combination with BTKi in this study might open a way for a novel treatment strategy in clinical trials. Citation Format: Xiaodan Hou, Honghua Yan, Xin Zhang, Weidong Qian, Dong Chen, Zhihua Ren, Youzhi Tong. GT0486, a novel mTORC1/2 dual inhibitor, exhibits synergistic antitumor efficacy in combination with BTK inhibitors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6509.