AZD4956，一种强效且选择性的DNA聚合酶theta抑制剂，在HRR缺陷细胞背景中增强DNA损伤剂的活性并改善新一代PARP1选择性抑制剂saruparib的疗效

Introduction: Loss-of-function mutations in the tumour suppressors BRCA1 / BRCA2 inactivate the homologous recombination repair (HRR) pathway, driving genomic instability and cancer progression but conferring sensitivity to DNA double-strand break-inducing agents such as platinum salts and poly(ADP-ribose) polymerase inhibitors (PARPi). BRCA1 / BRCA2 mutations are frequent in ovarian, breast, pancreatic, and prostate cancers, underpinning approvals of PARPi in these settings. Despite strong activity in HRR-defective tumours, PARPi responses vary and resistance emerges. Attempts to boost efficacy by combining PARPi with other DNA damage response inhibitors have been limited by enhanced myelosuppression, constraining dose intensity and benefit. Results: AZD4956 is a novel, potent, and selective inhibitor of the polymerase activity of DNA polymerase theta (Polθ), a key effector of microhomology-mediated end joining-a repair pathway critical when HRR is compromised. Combining AZD4956 with the PARP1-selective inhibitor saruparib improves efficacy versus either agent alone across HRR-defective cellular backgrounds, with no activity in HRR-proficient settings. Enhanced efficacy correlates with increased genomic instability: in HRR-deficient cells, the combination produces a ~4-fold rise in chromosomal aberrations. AZD4956 also potentiates other DNA-damaging agents (e.g., cisplatin, TOP1 inhibitors) specifically in HRR-deficient lines.AZD4956 shows single-agent in vitro activity in the low-nanomolar range in cell lines with PALB2 , BRCA2 , and RAD51C mutations, like PARPi, but no single-agent activity in BRCA1 -mutant cells. In vivo , AZD4956 monotherapy yields modest tumour growth inhibition (TGI ~50-80%) in some BRCA2 and PALB2 mutant models. By contrast, AZD4956 (≥10 mg/kg BID) combined with the maximal efficacious mouse dose of saruparib (1 mg/kg QD) consistently outperforms either monotherapy. Increased efficacy aligns with pharmacodynamic modulation: the combination drives an average ~2-fold increase in micronuclei in red blood cells versus monotherapy. Combination activity is observed in both BRCA1 - and BRCA2 -mutant patient-derived xenografts from diverse tissues (breast, prostate) and is restricted to HRR-deficient models where PARPi alone confers some TGI. Notably, maximal combination benefit requires the maximal efficacious saruparib dose. Conclusions: Preclinical pharmacology supports AZD4956 selectivity and its potential to amplify antitumour activity when combined with PARPi in HRR-defective cancers. AZD4956 is being evaluated in PARTHENON, a first-in-human, open-label, multicentre, phase 1/2a study of AZD4956 plus saruparib in patients with HRR-deficient solid tumours.