Inhibition of BCL-2 and MCL-1 disrupts mitochondrial respiration and overcomes radioresistance in choroidal melanoma.

Choroidal melanoma is the most common primary intraocular malignancy in adults. Radioresistance is a major therapeutic obstacle in choroidal melanoma with underlying mechanisms poorly understood. In this study, we established radioresistant OCM-3-r and 92-1-r cell lines and identified upregulation of BCL-2 as a key survival mechanism. BCL-2 knockdown impaired mitochondrial respiration, reduced ATP production, and induced apoptosis. Pharmacological inhibition with venetoclax recapitulated these effects in resistant cells, suppressing mitochondrial function and triggering dose-dependent apoptosis. In vivo, venetoclax significantly inhibited tumor growth without affecting body weight and increased cleaved caspase-3 expression in xenografts. However, venetoclax alone did not improve survival. Combination therapy with venetoclax and the MCL-1 inhibitor MIK665 exhibited strong synergy, resulting in enhanced tumor regression and significantly prolonged survival. These findings demonstrate that dual inhibition of BCL-2 and MCL-1 effectively overcomes radioresistance in choroidal melanoma by disrupting mitochondrial function and promoting apoptosis.