Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
Expert Opin Drug Saf. 2022 Apr;21(4):447-451. doi: 10.1080/14740338.2022.2047176. Epub 2022 Mar 15.
PARP inhibitors have dramatically improved outcomes for ovarian cancer patients, transforming oncologists' armamentarium and fueling hope for more cures and longer survival.
The recent PARP inhibitor randomized trials of FDA approved PARP inhibitors for ovarian cancer, olaparib, rucaparib and niraparib, and implications for clinical care are discussed with a focus on toxicity and risks. PARP adds NAD polymers to DNA-binding proteins, improving survival of cells after DNA damage, and acting as a scaffold for important DNA Damage Response (DDR) enzymes. If this system is inhibited, PARP activation cannot support DNA repair when there is synthetic lethality from mutations or homologous repair dysfunction (HRD), and the accumulation of DNA damage can kill cancer and lead to the catastrophic complications of MDS/AML. Although the risk of AML can be a < 1% risk, the incidence of MDS/AML presently approaches 10% in patients with mutations, multiple prior lines of platinum therapy, and protracted exposure to PARP inhibitors.
PARP inhibitors are a well-tolerated and exciting new class of agents that improve survival despite the risk of AML. Understanding of the biology has led to optimal use and potential new strategies for overcoming PARP resistance.
聚腺苷二磷酸核糖聚合酶（PARP）抑制剂显著改善了卵巢癌患者的预后，改变了肿瘤学家的治疗手段，并为更多的治愈方法和更长的生存时间带来了希望。
本文讨论了最近 FDA 批准的用于卵巢癌的 PARP 抑制剂奥拉帕利、鲁卡帕利和尼拉帕利的随机临床试验结果及其对临床治疗的影响，重点关注毒性和风险。PARP 会将 NAD 多聚体添加到 DNA 结合蛋白上，从而在 DNA 损伤后提高细胞的存活率，并作为重要的 DNA 损伤反应（DDR）酶的支架。如果该系统受到抑制，当存在突变或同源重组修复功能障碍（HRD）导致合成致死性时，PARP 激活将无法支持 DNA 修复，并且 DNA 损伤的积累会杀死癌症并导致骨髓增生异常综合征/急性髓系白血病（MDS/AML）等灾难性并发症。尽管 AML 的风险可能低于 1%，但目前在携带突变、多次铂类化疗和长期暴露于 PARP 抑制剂的患者中，MDS/AML 的发病率接近 10%。
PARP 抑制剂是一类耐受性良好且令人兴奋的新型药物，尽管存在 AML 风险，但能提高生存率。对生物学的认识已导致其得到了最佳应用，并为克服 PARP 耐药性提供了新的策略。
