TR-107, a novel mitochondrial ClpP activator, exhibits potent antitumor activity in adrenocortical carcinoma models

Adrenocortical carcinoma (ACC) is a rare, aggressive malignancy arising from the adrenal cortex with limited effective treatment options. The pathophysiology of ACC is characterized by aberrant steroidogenesis and mitochondrial enrichment, reflecting the central role of mitochondria in adrenal steroid hormone synthesis and tumor metabolism. We hypothesized that therapeutically targeting mitochondrial function could yield enhanced antitumor activity in ACC. To test this, we evaluated TR-107, a novel small-molecule agonist of the mitochondrial protease ClpP, which disrupts mitochondrial proteostasis and bioenergetics. TR-107 exhibited potent cytotoxicity at low nanomolar concentrations in NCI-H295R cells (IC₅₀ ≈ 24 nM) and in ACC patient-derived organoids (PDOs) (IC₅₀ ≈ 15 nM), significantly reducing cell viability and confluency in vitro . EdU-based flow cytometry demonstrated reduced S-phase populations and cell size following 48-hour TR-107 treatment, consistent with G1 and G2 arrest. Annexin V/PI assays revealed increased early and late apoptotic fractions in treated ACC cells, confirming apoptotic cell death. Similarly, ACC PDOs and patient-derived xenograft organoids (PDXOs) exhibited substantial decreases in viability upon ClpP activation. Given the high expression of IGF-2 and IGF-1R signaling in ACC, we next examined the combinatorial potential of TR-107 with IGF-1R inhibition. Co-treatment produced synergistic reductions in viability across NCI-H295R cells and PDOs. Collectively, these findings identify mitochondrial ClpP activation as a promising therapeutic strategy for ACC and demonstrate that TR-107 exerts potent antitumor activity as a monotherapy or in combination with IGF-1R blockade. These results provide strong preclinical support for advancing ClpP agonists toward clinical development for the treatment of ACC.