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引用次数: 0
摘要
导言:随着对肿瘤生物学认识的不断深入,人们发现了癌症发生和发展的特征,其中包括 DNA 损伤修复(DDR)机制失调。利用潜在的肿瘤基因组不稳定性和肿瘤特异性 DDR 缺陷,聚(ADP-核糖)聚合酶(PARP)抑制剂(PARPi)诱导的 DNA 损伤成为一种新的非化疗治疗机会。PARPi目前已被批准用于多种肿瘤类型,其中同源重组修复(HRR)缺陷的肿瘤获益最大,包括BRCA1/2基因(BRCA)和其他通路成员(如PALB2和Rad51c)的种系突变和体细胞突变:这篇综述文章概述了目前的批准情况以及已知和提出的 PARPi 耐药机制。此外,文章还讨论了克服PARPi耐药性的治疗策略,包括正在进行的临床试验:PARPi已被证明是一种安全有效的疗法,是多种实体瘤类型治疗的基石。阐明先天和后天的耐药性机制,加上利用 PARPi 的活性、预防或逆转耐药性的新型治疗方案的出现,为进一步扩大 PARPi 在癌症治疗中的作用提供了机会。
Strategies for the prevention or reversal of PARP inhibitor resistance.
Introduction: Advances in our understanding of tumor biology shed light on hallmarks of cancer development and progression that include dysregulated DNA damage repair (DDR) machinery. Leveraging the underlying tumor genomic instability and tumor-specific defects in DDR, Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induced DNA damage emerges as a novel non-chemotherapy therapeutic opportunity. PARPis are currently approved in multiple tumor types, with the largest benefit seen in tumors with homologous recombination repair (HRR) deficiency, including germline and somatic mutations in BRCA1/2 genes (BRCA) and other pathway members such as PALB2 and Rad51c.
Areas covered: This review article summarizes the current approval landscape and known and proposed mechanisms of resistance to PARPi. Further, therapeutic strategies to overcome PARPi resistance are discussed, including ongoing clinical trials.
Expert opinion: PARPi have proven to be a safe and effective therapy and represents a cornerstone treatment across multiple solid tumor types. Elucidating innate and acquired mechanisms of resistance, coupled with the emergence of novel therapeutic options to capitalize on the activity of PARPi and prevent or reverse the acquisition of resistance, provides an opportunity to further expand the role of PARPi in cancer therapy.
期刊介绍:
Expert Review of Anticancer Therapy (ISSN 1473-7140) provides expert appraisal and commentary on the major trends in cancer care and highlights the performance of new therapeutic and diagnostic approaches.
Coverage includes tumor management, novel medicines, anticancer agents and chemotherapy, biological therapy, cancer vaccines, therapeutic indications, biomarkers and diagnostics, and treatment guidelines. All articles are subject to rigorous peer-review, and the journal makes an essential contribution to decision-making in cancer care.
Comprehensive coverage in each review is complemented by the unique Expert Review format and includes the following sections:
Expert Opinion - a personal view of the data presented in the article, a discussion on the developments that are likely to be important in the future, and the avenues of research likely to become exciting as further studies yield more detailed results
Article Highlights – an executive summary of the author’s most critical points.