SDHB deficiency silences ABCB1 expression and confers therapeutic vulnerability across multiple cancer types

Abstract

Succinate dehydrogenase B (SDHB)-deficient cancers, including pheochromocytoma and paraganglioma (PPGL), renal cell carcinoma (RCC), and gastrointestinal stromal tumor (GIST), exhibit aggressive clinical behavior with limited treatment options. To identify novel therapeutic vulnerabilities, we performed high-throughput drug screening using co-cultured human SDHB-deficient and SDHB-reconstituted UOK269 human renal cell carcinoma cells with dual fluorescence labeling. Several compounds displaying preferential cytotoxicity toward SDHB-deficient cells were known substrates of the ATP-binding cassette B1 (ABCB1) transporter, also known as Multidrug Resistance Protein 1 (MDR1). Accordingly, SDHB-deficient cells demonstrated markedly reduced ABCB1 expression, a phenotype confirmed across human SDHB-deficient PPGL, RCC, and GIST samples, but absent in IDH- or FH-deficient tumors. Mechanistic investigation revealed that KDM4A histone demethylase is downregulated in SDHB-deficient tumors, and KDM4A loss (or inhibition) is sufficient to reduce ABCB1 expression, globally increase H3K9me3 levels, and sensitize cells to cytotoxic ABCB1 substrates. TCGA analysis confirmed correlated KDM4A-ABCB1 expression in SDHB-deficient cancers, with ABCB1 levels predicting drug sensitivity across cancer cell lines. Clinical analysis demonstrated that SDHB-mutant PPGL patients treated with vincristine-containing chemotherapy exhibited significantly longer progression-free survival compared to non-SDHB patients. These findings establish a novel metabolic-epigenetic pathway linking SDHB deficiency to ABCB1 silencing and provide rational basis for repurposing vincristine, and related ABCB1 substrate vinca alkaloids, across SDHB-deficient cancer types; offering an alternative precision treatment approach for these challenging malignancies.