Synergistic strategies: ADC-PARP inhibitor combinations in triple-negative breast cancer therapy

IF 2.9 4区医学 Q2 PATHOLOGY

Pathology, research and practice Pub Date : 2025-06-04 DOI:10.1016/j.prp.2025.156075

Mokhtar Rejili

{"title":"Synergistic strategies: ADC-PARP inhibitor combinations in triple-negative breast cancer therapy","authors":"Mokhtar Rejili","doi":"10.1016/j.prp.2025.156075","DOIUrl":null,"url":null,"abstract":"<div><div>Triple-negative breast cancer (TNBC) continues to be a very aggressive subtype with few targeted therapy options. Antibody-drug conjugates (ADCs) and poly (ADP-ribose) polymerase inhibitors (PARPis) have been promising therapeutic strategies, each of which targets different vulnerabilities in TNBC cells. ADCs like sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) target cytotoxic payloads with specificity, whereas PARPis like olaparib, rucaparib, niraparib, and talazoparib cause synthetic lethality in homologous recombination repair (HRR)-deficient tumors. Recent clinical trials of SEASTAR and PETRA have evaluated ADC-PARPi combinations to enhance anti-tumor activity through DNA damage induction with the prevention of its repair. Early data demonstrate enhanced therapeutic outcomes, especially in BRCA-mutated and HRD-positive TNBC. Myelosuppression and adaptation of dosing regimens remain challenges to be addressed. Future directions include biomarker-driven patient selection, combination with immune checkpoint inhibitors, and advancement in next-generation ADCs. The synergistic potential of ADC-PARPi combinations provides a new avenue for overcoming TNBC resistance, enhancing treatment outcomes, and widening therapeutic strategies for this challenging disease.</div></div>","PeriodicalId":19916,"journal":{"name":"Pathology, research and practice","volume":"272 ","pages":"Article 156075"},"PeriodicalIF":2.9000,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Pathology, research and practice","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0344033825002687","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"PATHOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Triple-negative breast cancer (TNBC) continues to be a very aggressive subtype with few targeted therapy options. Antibody-drug conjugates (ADCs) and poly (ADP-ribose) polymerase inhibitors (PARPis) have been promising therapeutic strategies, each of which targets different vulnerabilities in TNBC cells. ADCs like sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) target cytotoxic payloads with specificity, whereas PARPis like olaparib, rucaparib, niraparib, and talazoparib cause synthetic lethality in homologous recombination repair (HRR)-deficient tumors. Recent clinical trials of SEASTAR and PETRA have evaluated ADC-PARPi combinations to enhance anti-tumor activity through DNA damage induction with the prevention of its repair. Early data demonstrate enhanced therapeutic outcomes, especially in BRCA-mutated and HRD-positive TNBC. Myelosuppression and adaptation of dosing regimens remain challenges to be addressed. Future directions include biomarker-driven patient selection, combination with immune checkpoint inhibitors, and advancement in next-generation ADCs. The synergistic potential of ADC-PARPi combinations provides a new avenue for overcoming TNBC resistance, enhancing treatment outcomes, and widening therapeutic strategies for this challenging disease.

查看原文本刊更多论文

协同策略：ADC-PARP抑制剂联合治疗三阴性乳腺癌

三阴性乳腺癌（TNBC）仍然是一种非常具有侵略性的亚型，很少有靶向治疗选择。抗体-药物偶联物（adc）和聚（adp -核糖）聚合酶抑制剂（PARPis）一直是很有希望的治疗策略，它们各自针对TNBC细胞的不同脆弱性。adc如sacituzumab govitecan （SG）和datopotamab deruxtecan （Dato-DXd）特异性靶向细胞毒性有效载荷，而PARPis如olaparib、rucaparib、niraparib和talazoparib在同源重组修复（HRR）缺陷肿瘤中导致合成致死。最近的SEASTAR和PETRA临床试验已经评估了ADC-PARPi组合通过DNA损伤诱导和防止其修复来增强抗肿瘤活性。早期数据显示治疗效果增强，特别是brca突变和hrd阳性TNBC。骨髓抑制和给药方案的适应仍然是需要解决的挑战。未来的方向包括生物标志物驱动的患者选择，与免疫检查点抑制剂的联合，以及下一代adc的进展。ADC-PARPi联合的协同潜力为克服TNBC耐药、提高治疗效果和扩大这种具有挑战性的疾病的治疗策略提供了新的途径。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Pathology, research and practice 医学-病理学

CiteScore

5.00

自引率

3.60%

发文量

405

审稿时长

24 days

期刊介绍： Pathology, Research and Practice provides accessible coverage of the most recent developments across the entire field of pathology: Reviews focus on recent progress in pathology, while Comments look at interesting current problems and at hypotheses for future developments in pathology. Original Papers present novel findings on all aspects of general, anatomic and molecular pathology. Rapid Communications inform readers on preliminary findings that may be relevant for further studies and need to be communicated quickly. Teaching Cases look at new aspects or special diagnostic problems of diseases and at case reports relevant for the pathologist''s practice.