Elimusertib (AZD7648; AstraZeneca) is a potent, selective, orally bioavailable inhibitor of DNA-dependent protein kinase catalytic subunit (DNA-PKcs, encoded by PRKDC). DNA-PKcs is the enzymatic core of the DNA-PK holoenzyme, assembled at DSB termini by the Ku70/Ku80 heterodimer; it autophosphorylates at Ser2056/Thr2609 and phosphorylates downstream classical NHEJ effectors (XRCC4, LIG4, Artemis, PAXX) to execute DSB end-joining. Elimusertib blocks this catalytic activity, preventing c-NHEJ-mediated DSB repair. The mechanistic rationale in SDH-deficient tumors is a third-order synthetic lethality built on the BRCAness framework (Mechanisms 14, 18, 28). SDH loss → succinate accumulation → competitive inhibition of α-KG-dependent KDM4A and KDM4B histone demethylases at DSB sites → H3K9me3 persistence → impaired TIP60 acetyltransferase and ATM kinase recruitment → HR repair deficiency (BRCAness) in all SDH-deficient cells regardless of BRCA1/2 status (Sulkowski et al., Nat Genet 2018, PMID 30013182; Nature 2020, PMID 32494005). In HR-deficient cells, c-NHEJ — mediated by the DNA-PK complex — becomes the primary remaining DSB repair pathway. Elimusertib inhibits DNA-PKcs and removes this backup, causing catastrophic unrepaired DSB accumulation selectively in BRCAness-positive cells. HR-proficient cells tolerate DNA-PKcs inhibition by routing DSBs through HR, creating the therapeutic window. Key preclinical evidence establishing BRCAness selectivity: Anastasia et al. (Mol Cancer Ther 2022, PMID 35149547) tested AZD7648 in BRCA-deficient versus BRCA-proficient ovarian cancer patient-derived xenograft (OC-PDX) models. AZD7648 significantly potentiated pegylated liposomal doxorubicin and olaparib in BRCA-deficient OC-PDX tumors — preventing abdominal metastases, reducing tumor burden, and improving survival — but produced no potentiation in BRCA-proficient OC-PDX controls. This directly validates the BRCAness-selective mechanism: DNA-PKcs inhibition is inert in HR-proficient cells but synthetic-lethal in HR-deficient (BRCAness-positive) cells. The same selectivity principle applies to BRCAness-positive SDH-deficient tumors. Contextual radiation sensitivity data: Berman et al. (Cancers 2026, PMID 42650014) reported 66.7% objective response rate and 100% disease control rate in 12 SDH-deficient GIST patients treated with Y-90 SIRT for hepatic metastases at 32-month median follow-up. The authors attributed this sensitivity to properties of SDH-deficient biology — consistent with BRCAness-driven impaired DSB repair rendering these tumors more vulnerable to radiation-induced DSBs. This observation directly contextualizes DNA-PKcs inhibition: if SDH-deficient cells are already radiation-sensitive (reflecting deficient DSB repair), further blocking c-NHEJ backup via elimusertib amplifies this vulnerability pharmacologically. Mechanistic distinctions from other DDR drugs in this engine: PARP inhibitors (olaparib/niraparib, Mechanism 14) trap PARP at SSBs → SSBs collapse into DSBs at replication forks → HR-deficient cells cannot resolve them; elimusertib prevents c-NHEJ from resolving the resulting DSBs — complementary mechanisms. ART558 (POLQ inhibitor, Mechanism 18) blocks TMEJ/alt-EJ, an error-prone microhomology-mediated backup mechanistically distinct from c-NHEJ. Prexasertib (CHK1 inhibitor, Mechanism 28) targets the replication fork stabilization checkpoint, not the DSB repair step itself. All four are non-redundant in BRCAness-positive cells. Clinical context: NCT03907969 was a Phase 1/2a open-label dose-escalation study of AZD7648 monotherapy or in combination with cytotoxic chemotherapy or novel anti-cancer agents in patients with advanced malignancies (n=30; AstraZeneca; status: COMPLETED). The AZD7648 + olaparib combination arm is the most directly relevant to the SDH-BRCAness context given Anastasia et al.'s preclinical data. Key limitation: No published data directly test elimusertib in SDH-deficient GIST, PPGL, or RCC cell lines or xenograft models. The mechanistic case rests on (1) the Sulkowski BRCAness mechanism (PMID 30013182, 32494005), (2) Anastasia et al.'s BRCA-deficient-selective AZD7648 preclinical data (PMID 35149547), and (3) Berman et al.'s SDH-GIST radiation sensitivity observation (PMID 42650014). Direct in vitro validation in isogenic SDH-null versus SDH-intact lines is the required next step.