Ym155 (sepantronium bromide) suppresses transcription of BIRC5 (survivin) by displacing the transcription factor Sp1 from the CDE/CHR elements in the BIRC5 promoter, reducing survivin mRNA and protein levels. The mechanistic rationale for selectivity in SDH-deficient tumors rests on two converging lines. First, SDH loss drives pseudohypoxic HIF-1α stabilization (via succinate-mediated PHD inhibition), and the BIRC5 promoter contains canonical HRE elements through which HIF-1α transcriptionally upregulates survivin above the already-elevated baseline found in most cancers. Second, SDH-deficient cells accumulate unrepaired DNA double-strand breaks via the KDM4B/H3K9me3 BRCAness mechanism (Mechanism 14). In wild-type cells, such DNA damage triggers caspase-mediated apoptosis; in SDH-deficient cells, HIF-1α-driven survivin elevation suppresses caspase-3/7 and forms a ternary anti-apoptotic complex with XIAP and caspase-9, allowing cells to tolerate an otherwise lethal DNA damage load. Ym155 targets both functions simultaneously: depleting survivin removes both the apoptosis block and the CPC/spindle checkpoint support on which genomically unstable SDH-deficient cells depend for mitotic fidelity. Primary SDH-selective mechanism (directly established): Guo et al. (PMID 41711310, Endocr Relat Cancer 2026-03; DOI 10.1530/ERC-25-0397) used isogenic SDHB-KO vs SDHB-WT UOK269 RCC cells to demonstrate that YM155 is selectively lethal in SDH-deficient cells via ROS-induced DNA damage. The mechanism for this selectivity was directly established: SDH loss → succinate → KDM4A/KDM4B histone demethylase inhibition → impaired DNA repair → YM155-generated ROS/DNA damage cannot be resolved → selective cell death. Critically, genetic inhibition of KDM4 alone (independent of SDH loss) fully recapitulated the SDH-specific sensitivity, proving that KDM4-mediated repair impairment is the mechanistic basis — not primarily HIF-1α-driven survivin elevation. The finding was validated in four independent models: isogenic SDHB-KO/WT RCC cells, primary human pheochromocytoma cells, mouse pheochromocytoma (MPC) cells, and primary SDHB-deficient mouse kidney cells; chemical inhibition of SDH activity with two independent inhibitors produced identical sensitivity. This validates YM155 as a multi-mechanism agent in SDH-deficient tumors: the survivin/apoptosis-evasion axis (HIF-1α→BIRC5, described above) is reinforced by an orthogonal SDH-KDM4-DNA repair synthetic lethality. Clinical data: Phase 2 data in relapsed/refractory non-Hodgkin lymphoma (NCT00390117) showed partial responses with survivin suppression confirmed pharmacodynamically; dose-limiting toxicity includes renal impairment at higher doses, manageable with adequate hydration. Key limitations: (1) no dedicated SDH-deficient tumor trial exists; (2) the specific degree of HIF-1α-driven BIRC5 upregulation in SDH-deficient GIST versus PPGL models has not been measured; (3) Ym155 showed limited single-agent activity in Phase 2 solid tumor studies (NCT00437957), suggesting combination strategies or patient selection by BIRC5 expression/HIF-1α level may be required.