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

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.