来源于PARP抑制剂预处理的乳腺癌和卵巢癌患者的一组PDX模型的表征及其治疗评估

Introduction: Poly (ADP‑ribose) polymerase (PARP) inhibitors benefit patients with homologous recombination-deficient cancers, especially BRCA‑mutated, but resistance frequently emerges through multiple adaptive mechanisms, limiting long‑term efficacy. To better recapitulate clinical resistance and advance precision therapy development, we established a panel of patient‑derived xenograft (PDX) models from PARP inhibitors pretreated breast and ovarian cancers, providing a translational platform to investigate resistance mechanisms and assess novel treatment strategies. Methods: Ten PDX models from patients pretreated with PARP inhibitors (Olaparib, Niraparib ± Bevacizumab), and Talazoparib + Avelumab) were established subcutaneously in immunodeficient mice (NOD.SCID, BALB/c nude, NSG-like) and characterized by histology and RNA sequencing. Homologous recombination-related alterations (BRCA1/BRCA2 mutations, PALB2 deletions) were present in some patients, and all had disease progression after PARP inhibitor therapy. For in vivo efficacy studies, three breast cancer PDX models were treated with Olaparib (100 mg/kg, p.o., QD) for 3-5 weeks following clinical schedule. Tumor growth inhibition (TGI) was calculated as [1 - (mean treated tumor volume / mean control tumor volume)] * 100%. Homologous recombination deficiency (HRD) scores from whole exome sequencing via scarHRD and PureCN used a cutoff of 38; high HRD scores (≥38) correlated with PARP inhibitors sensitivity. Results: A panel of PAPR inhibitor clinical pretreated PDX models, including three breast cancer (BR9671, BR9679, BR9815) and seven ovarian cancer (OV9576, OV9670, OV9692, OV9563, OV9568, OV9803, OV9805), were established with comparable genomic profiles to the clinic. To evaluate the PARP inhibitor efficacy in vivo , BR9671, BR9679 and BR9815 derived from the same Olaparib‑treated BRCA1 mutated patient were re‑challenged with Olaparib. Tumor progression was observed in all three PDX models (TGI: BR9671=29.68%, BR9679=-9.30 %, BR9815=13.77%) despite high HRD scores (58, 59, and 64, respectively), indicating pronounced genomic instability. Besides, each model carried the MDM4-S367L mutation and had high MDM4 (BR9671: 3.654, BR9679: 3.755, BR9815: 4.539) and MDM2 (BR9671: 6.028, BR9679: 6.118, BR9815: 6.524) expression. As MDM2/MDM4 are known p53 suppressors, these findings suggest impaired p53 function may contribute to PARP inhibitor resistance; but further investigation is required. Conclusion: By developing this panel of clinically PARP inhibitor pretreated PDX models, we established a translational platform that reflects clinical disease progression. These models enable investigation of resistance mechanisms and evaluation of next-generation therapies and combinations, supporting preclinical decision-making.