PO.ET03.03 · 实验与分子治疗
BRCA1缺陷三阴性乳腺癌中获得性saruparib (AZD5305)耐药对DNA损伤应答靶向疗法敏感
Acquired saruparib (AZD5305) resistance in BRCA1-deficient triple negative breast cancer is vulnerable to DNA damage response-targeted therapeutics
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
用于合成致死杀伤BRCA1/2缺陷癌症的poly (ADP)-ribose polymerase (PARP)抑制剂(PARPi)的开发，彻底改变了BRCA1/2缺陷患者的前景和生存。PARPi现已常用于治疗BRCA1/2缺陷或同源重组(HR)缺陷的乳腺癌、卵巢癌、前列腺癌和胰腺癌。尽管取得了这一临床成功，仍有30-40%的BRCA1/2缺陷患者对PARPi无应答，而绝大多数最初有应答的患者最终会产生PARPi耐药。这代表着限制PARPi治疗临床影响的重大挑战。理解PARPi耐药机制对于为内在性和获得性PARPi耐药癌症开发更好的治疗策略至关重要。为更好地治疗BRCA1/2缺陷癌症并对抗PARPi耐药，近期的努力促成了saruparib (AZD5305)的开发，这是一种PARP1特异性抑制剂，由于对其他PARP家族成员的脱靶抑制有限、因而毒性降低，具有显著改善的安全性特征。Saruparib目前正在进行3期临床试验，预计将成为BRCA1/2缺陷和HR缺陷癌症患者的标准治疗PARPi。我们从亲本BRCA1缺陷MDA-MB-436三阴性乳腺癌(TNBC)细胞中构建了5个saruparib耐药(SR)细胞系，其对saruparib耐药超过1000倍，但对其他非特异性临床PARPi表现出差异性敏感性。SR细胞系在应对saruparib和非特异性PARPi talazoparib时表现出细胞PARP活性抑制和PARP捕获的改变。全基因组测序在每个SR细胞系中识别出PARP1活性位点突变，这些突变体的体外重建提示它们驱动了对saruparib的耐药以及对其他非特异性临床PARPi的敏感性改变。重要的是，尽管获得了saruparib耐药，SR细胞系仍保留对其他DNA损伤应答靶向疗法的敏感性。总之，这项工作表征了我们认为是首个BRCA1缺陷获得性saruparib耐药模型，并揭示了可能为理性联合策略和针对临床上saruparib治疗进展患者的新型治疗方法提供依据的脆弱性。
查看英文原文 English abstract
The development of poly (ADP)-ribose polymerase (PARP) inhibitors (PARPi) for the synthetic lethal killing of BRCA1/2-deficient cancers revolutionized BRCA1/2-deficient patient outlook and survival. PARPi are now commonly used to treat BRCA1/2-deficient or homologous recombination (HR)-deficient breast, ovarian, prostate, and pancreatic cancers. Despite this clinical success, 30-40% of BRCA1/2-deficient patients do not respond to PARPi and the vast majority that do initially respond, ultimately develop PARPi resistance. This represents a major challenge limiting the clinical impact of PARPi treatment. Understanding PARPi resistance mechanisms is essential for developing better treatment strategies for intrinsic and acquired PARPi-resistant cancers. Recent efforts to better treat BRCA1/2-deficient cancers and combat PARPi resistance led to the development of saruparib (AZD5305), a PARP1-specific inhibitor with significantly improved safety profiles due to limited off-target inhibition of other PARP family members and hence reduced toxicity. Saruparib is currently undergoing phase 3 clinical trials and is anticipated to be the standard of care PARPi for BRCA1/2- and HR-deficient cancer patients. We have generated 5 saruparib-resistant (SR) cell lines from parental BRCA1-deficient MDA-MB-436 triple negative breast cancer (TNBC) cells that are >1000-fold resistant to saruparib but exhibit differential sensitivity to other nonspecific clinical PARPi. SR cell lines exhibit altered inhibition of cellular PARP activity and PARP trapping in response to saruparib and the nonspecific PARPi talazoparib. Whole genome sequencing identified PARP1 active site mutations in each SR cell line, and in vitro reconstitution of these mutants suggests that they are driving resistance to saruparib and altered sensitivity to other nonspecific clinical PARPi. Importantly, despite acquired saruparib resistance, SR cell lines retain sensitivity to other DNA damage response targeted therapeutics. Collectively, this work characterizes what we believe to be the first BRCA1-deficient models of acquired saruparib resistance and uncovers vulnerabilities that may inform rational combination strategies and novel therapeutic approaches for patients who progress on saruparib in the clinic.
利益披露 Disclosure
M. R. Jordan, None..
P. S. VanderVere-Carozza, None.