A TROP2-targeting ADC synergizes with oxidative phosphorylation inhibitor to enhance apoptosis in ESCC by suppressing the PI3K-AKT-mTOR signaling pathway.

Currently, there are no effective targeted therapies for advanced esophageal squamous cell carcinoma (ESCC). Trophoblast cell surface antigen-2 (TROP2) are considered robust therapeutic targets which leverages antibody-drug conjugates (ADCs) to control solid tumors. Mitochondrial oxidative phosphorylation (OXPHOS) influences the growth of cancer cells, metastasis, and drug resistance. However, whether inhibiting OXPHOS can potentiate the efficacy of TROP2-targeting ADCs is not well understood. Here, we investigated the therapeutic efficacy of IMMU132 (IMMU), an ADC targeting TROP2, either alone or in combination with IACS010759 (IACS), a selective OXPHOS inhibitor, through clinically ESCC models. Immunohistochemical analysis was performed on a cohort of 222 patients, which revealed that 94.6% of all specimens tested positive for TROP2. Among them, moderate and strong staining were observed in 29.3% and 27.0% of cases, respectively. Co-administration of IMMU and IACS synergistically inhibited the growth of tumors in human ESCC cell lines, PDXO, and PDX models. Mechanistically, we found that the combination treatment achieved tumor suppression in ESCC cells via inducing apoptosis and oxidative stress, as well as preventing cell motility. Results of the RNA-seq analysis demonstrated that the combined treatment of IMMU and IACS downregulated the expression level of several cancer-related pathways, such as the PI3K-AKT-mTOR pathway, OXPHOS, and apoptosis. Moreover, the data confirmed that inhibition of the PI3K-AKT-mTOR pathway significantly suppressed ESCC tumor growth following administration of the combination therapy. Based on these findings, we present a novel therapeutic strategy that enhances the efficacy of TROP2-targeting ADCs via concurrent inhibition of OXPHOS, which is likely to improve clinical outcomes of patients with TROP2-positive ESCC.