Peposertib (M3814; Merck KGaA/EMD Serono) is an oral, selective, ATP-competitive inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs, PRKDC), inhibiting DNA-PKcs autophosphorylation at Thr2609 and blocking canonical non-homologous end-joining (NHEJ) of DNA double-strand breaks (DSBs). The SDH-specific rationale derives directly from the BRCAness phenotype established by Sulkowski et al. (Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005): SDH loss → succinate accumulation → competitive inhibition of α-KG-dependent KDM4A and KDM4B histone demethylases → H3K9me3 persistence at DSB chromatin → impaired TIP60 acetyltransferase and ATM kinase recruitment → defective homologous recombination (HR) repair in all SDH-deficient tumor cells. In cells with intact HR, DSBs are partitioned between HR (preferred in S/G2 phases) and canonical NHEJ. In HR-deficient BRCAness-positive cells, NHEJ becomes the dominant and often sole mechanism for DSB resolution. DNA-PKcs, together with the Ku70/Ku80 heterodimer, forms the DNA-PK holoenzyme at DSB ends. DNA-PKcs synapses DSB ends, phosphorylates H2AX (γ-H2AX mark), recruits and activates ARTEMIS nuclease for 5'/3' overhang processing, and enables ligation by the XRCC4-DNA ligase IV-XLF complex. Inhibiting DNA-PKcs with peposertib in BRCAness-positive SDH-deficient cells removes this compensatory NHEJ backup — HR is already constitutively impaired by the succinate-KDM4B-H3K9me3 mechanism — and DSBs accumulate lethally. HR-proficient SDH-intact cells retain the ability to repair DSBs via HR and are substantially less sensitive to DNA-PKcs inhibition, providing the therapeutic window. This direction is mechanistically distinct from all other BRCAness-targeted entries in this engine: PARP inhibitors (olaparib/niraparib, Mechanism 14) trap PARP1 at single-strand breaks that collapse to DSBs, and those DSBs cannot be repaired by impaired HR; POLQ inhibitor (ART558, Mechanism 18) blocks the alt-EJ/TMEJ backup pathway (not canonical NHEJ); CHK1 inhibitor (prexasertib, Mechanism 28) targets the replication stress checkpoint effector rather than a DSB repair pathway. Peposertib targeting canonical NHEJ adds a fourth orthogonal attack on the DSB repair failure that defines BRCAness-positive SDH-deficient tumors. A particularly compelling clinical rationale exists for the combination of peposertib with PRRT in SDH-deficient PPGL: (1) SDH-deficient PPGL are universally SSTR2-high (confirmed DOTATATE-PET; PMID 42454478), making them eligible for Lu-177 DOTATATE PRRT; (2) PRRT delivers targeted β/α-particle radiation directly to SSTR2+ cells, generating DSBs in the tumor; (3) BRCAness (Mechanism 14) impairs HR repair of those DSBs; (4) peposertib inhibits NHEJ repair of those same DSBs — creating triple DSB repair failure selectively in SSTR2-high, BRCAness-positive SDH-deficient cells. This mechanistic rationale is directly reflected in NCT04750954 (NCI Phase 1b; peposertib + Lu-177 DOTATATE in SSTR2+ GEP-NETs), which tests exactly this combination in a SSTR2+ neuroendocrine tumor population overlapping substantially with SDH-deficient PPGL. Key clinical data: NCT02516813 (Phase 1a/1b; M3814 + fractionated radiotherapy + cisplatin in advanced solid tumors; completed; n=52; Merck/EMD Serono) established peposertib safety and dosing in combination with radiation and a DNA-damaging agent — exactly the clinical scenario of interest. Zenke FT et al. (Mol Cancer Ther 2020, PMID 32265313) demonstrated that peposertib potentiates radiation-induced cytotoxicity and regresses human tumor xenografts as a single agent and in combination with radiation. Key limitations: (1) No published data test peposertib in any SDH-deficient cell line or xenograft model. (2) No SDH-genotype-stratified efficacy data exist from any peposertib trial. (3) The synthetic lethality of DNA-PK inhibition with the SDH-specific BRCAness phenotype is mechanistically motivated but requires direct experimental validation in isogenic SDHA-null/SDHB-KO cell lines. Evidence_score 28 (theoretical): well-anchored mechanistic chain from SDH loss through BRCAness to NHEJ dependency, with supporting peposertib clinical data in related contexts, but no SDH-specific experimental or clinical data.