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

SDHB-deficient UOK269 renal cell carcinoma cells show markedly reduced ABCB1 expression, and this ABCB1 silencing is linked to longer progression-free survival with vincristine in SDHB-mutant PPGL patients.

• Why it matters: SDHB-deficient cancers such as PPGL, RCC, and GIST are aggressive and have limited targeted options, motivating identification of vulnerabilities tied to SDHB loss.
• What they did: High-throughput drug screening with dual-fluorescence co-culture of SDHB-deficient versus SDHB-reconstituted UOK269 cells found preferential killing by ABCB1/MDR1 substrates; SDHB-deficient tumors showed reduced ABCB1, linked to downregulated KDM4A, where KDM4A loss or inhibition increased H3K9me3 and reduced ABCB1.
• The result: ABCB1 silencing was confirmed across human SDHB-deficient PPGL, RCC, and GIST samples but not IDH- or FH-deficient tumors, and TCGA plus cell-line analyses linked ABCB1 levels to drug sensitivity; in SDHB-mutant PPGL, vincristine-containing chemotherapy produced significantly longer progression-free survival than in non-SDHB patients.

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