Abstract 5681: Metabolic targeting of NRF2 potentiates the efficacy of TRAP1 inhibitor GTPP in colorectal cancer

Abstract Tumor necrosis factor receptor-associated protein 1 (TRAP1) is a mitochondrial homolog of HSP90 chaperones. It plays an important role in protection against oxidative stress and apoptosis by regulating reactive oxidative species (ROS) and may also exert the cytoprotective activities by regulating mitochondrial permeability transition pore opening. Recent studies have suggested that TRAP1 may regulate metabolism and mitochondrial homeostasis in cancer. To further elucidate the mechanistic role of TRAP1 in regulating tumor cell survival, we used cellular models to investigate cellular effects and signaling pathways regulated by TRAP1 in several colon cancer cell lines. Inhibition of TRAP1 by a small molecule inhibitor, Gamitrinib-triphenylphosphonium (GTPP), in colon cancer cells led to ROS production, ER stress, reduction of cell viability and induction of cell death. Interestingly, we observed wide-range of responses to TRAP1 inhibition among these colon cancer cell lines. In GTPP sensitive cell lines (SW48), GTPP induced upregulation of GRP78, CHOP and cleavage form PARP proteins. In contract, in GTPP resistant cells (DLD1 and RKO), GTPP treatment highly induced activation of antioxidant gene NRF2, leading to better cell survival under oxidative environment. NRF2 target genes HO1 and NQO1 were upregulated in GTPP-treated DLD1 cells, making these cells more resistant to GTPP treatment. Using reporter assay, we further found that transcriptional activation of antioxidative responds element (ARE) was increased in GTPP-treated DLD1 and RKO cells (GTPP resistant), but not in SW48 cells (GTPP sensitive). Combination of NRF2 inhibitor ML385 and GTPP led to excessive ROS production and exacerbated GTPP-induced cell death in GTPP resistant cells. These new findings for the first-time link TRAP1 and NRF2 in a common pathway regulating ROS production in colon cancer. Taken together, dual targeting of TRAP1 and NRF2 may potentially overcome the tumor cell resistance through disruption of mitochondrial redox homeostasis. Citation Format: Hong-Yuan Tsai, Ru Chen, Noah Shroyer, Sheng Pan. Metabolic targeting of NRF2 potentiates the efficacy of TRAP1 inhibitor GTPP in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5681.