Drug targeting of the monocarboxylate transporter MCT4 is a novel treatment strategy for metastatic ccRCC

Clear cell renal cell carcinoma (ccRCC) is characterized by a metabolic shift towards enhanced aerobic glycolysis and increased lactate production. The survival rate for metastatic RCC is still poor. We evaluated the lactate monocarboxylate transporter 4 (MCT4), encoded by SLC16A3, as drug target for metastatic disease. MCT4 protein expression in 209 distant ccRCC metastases, including 40 recurrent metastases, was generally as high as compared to primary tumor tissue and significantly increased compared to non-tumor tissue (P < 1E-15). MCT4 expression was irrespective of affected organs and mutations in RCC driver genes. DNA methylation in the SLC16A3 promoter, assessed by MALDI TOF mass spectrometry and correlated with clinicopathological data, were not significantly different in metastases of all investigated organ sites, and between paired tumor and metastases samples. Visualization of expression in single-cell and spatial RNA sequencing datasets reveals main expression of SLC16A3 in cells derived from tumor, tumor-normal interface, metastatic and lymph node tissue. Alone or combined with inhibition of mitochondrial respiration by metformin and phenformin, the MCT4 inhibitor syrosingopine significantly inhibits lactate efflux, induces cell viability reduction in four different RCC cell lines and patient-derived 2D/3D models, and alterations in cellular metabolism and mitochondrial respiration. Six patient-derived RCC air-liquid interface models, mimicking the complex RCC architecture, corroborate these data. Beyond potential prediction of patient outcome using MCT4 expression and DNA methylation at specific CpG sites, drug targeting of MCT4 and inhibiting mitochondrial respiration synergistically is a novel treatment strategy for metastatic ccRCC.