Rejili Mokhtar
Department of Biology, College of Sciences, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh 11623, Saudi Arabia.
Pathol Res Pract. 2025 Aug;272:156075. doi: 10.1016/j.prp.2025.156075. Epub 2025 Jun 4.
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.
三阴性乳腺癌（TNBC）仍然是一种侵袭性很强的亚型，几乎没有靶向治疗选择。抗体药物偶联物（ADC）和聚（ADP-核糖）聚合酶抑制剂（PARPi）一直是很有前景的治疗策略，它们各自针对TNBC细胞中的不同弱点。像戈沙妥珠单抗（SG）和德曲妥珠单抗（Dato-DXd）这样的ADC特异性靶向细胞毒性载荷，而像奥拉帕利、卢卡帕利、尼拉帕利和他拉唑帕利这样的PARPi在同源重组修复（HRR）缺陷的肿瘤中会导致合成致死。最近的SEASTAR和PETRA临床试验评估了ADC-PARPi联合用药，通过诱导DNA损伤并防止其修复来增强抗肿瘤活性。早期数据显示治疗效果有所增强，尤其是在BRCA突变和HRD阳性的TNBC中。骨髓抑制和给药方案的调整仍然是有待解决的挑战。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联合使用以及下一代ADC的进展。ADC-PARPi联合用药的协同潜力为克服TNBC耐药性、提高治疗效果以及拓宽针对这种具有挑战性疾病的治疗策略提供了一条新途径。
