聚（ADP-核糖）聚合酶 1 和 2 (PARP1/2) 抑制剂 (PARPi) 是批准用于同源重组修复 (HRR) 缺陷的乳腺癌、卵巢癌、胰腺癌和前列腺癌的靶向疗法。由于抑制 PARP1 足以导致同源重组缺陷 (HRD) 肿瘤的合成致死性，因此正在开发 PARP1 选择性抑制剂，例如 saruparib (AZD5305)。预计选择性 PARP1 抑制会产生更安全的特性，有利于其与其他 DNA 损伤修复抑制剂的组合。在这里，我们的目的是在患者来源的临床前模型中表征 AZD5305 与第一代 PARP1/2 抑制剂奥拉帕尼相比的抗肿瘤活性，并确定耐药机制。 13 个先前表征的患者来源的肿瘤异种移植 (PDX) 模型来自乳腺、携带 BRCA1、BRCA2 或 PALB2 种系致病性改变的卵巢癌和胰腺癌患者被用来评估单独使用 AZD5305 或与卡铂或共济失调性毛细血管扩张和 Rad3 相关 (ATR) 抑制剂 (ATR) 联合使用 AZD5305 的疗效，并将其与第一代 PARPi 奥拉帕尼。我们进行了 DNA 和 RNA 测序以及基于蛋白质的测定，以确定对任一 PARPi 的获得性耐药机制。就临床前完全缓解率而言，AZD5305 显示出优于第一代 PARPi 的抗肿瘤活性（75% vs. 37%）。与奥拉帕尼治疗组相比，AZD5305 治疗组的中位临床前无进展生存期显着更长（> 386 天与 90 天）。从机制上讲，AZD5305 在 PARPi 敏感肿瘤中比 PARP1/2 抑制剂奥拉帕尼诱导更多的复制应激和基因组不稳定性。所有使用 PARPi (39/39) 进行进展的肿瘤均显示出 RAD51 病灶形成导致 HRR 功能增加。已确定的最普遍的耐药机制是 BRCA1/BRCA2 回复突变的获得和亚效型 BRCA1 的积累。 AZD5305 不会使对奥拉帕尼获得性耐药的 PDX 敏感，但在 3/6 和 5/5 模型中分别与卡铂或 ceralasertib 联合使用时，会引起深刻而持久的反应。总的来说，这些结果表明新型 PARP1 选择性抑制剂 AZD5305 产生有效的抗肿瘤作用单独或与卡铂或 ceralasertib 联合使用，可以在具有 HRD 的 PDX 模型中产生反应，并延迟 PARPi 耐药性，这支持其在临床中作为一种新的治疗选择使用。© 2024。作者。

Poly (ADP-ribose) polymerase 1 and 2 (PARP1/2) inhibitors (PARPi) are targeted therapies approved for homologous recombination repair (HRR)-deficient breast, ovarian, pancreatic, and prostate cancers. Since inhibition of PARP1 is sufficient to cause synthetic lethality in tumors with homologous recombination deficiency (HRD), PARP1 selective inhibitors such as saruparib (AZD5305) are being developed. It is expected that selective PARP1 inhibition leads to a safer profile that facilitates its combination with other DNA damage repair inhibitors. Here, we aimed to characterize the antitumor activity of AZD5305 in patient-derived preclinical models compared to the first-generation PARP1/2 inhibitor olaparib and to identify mechanisms of resistance.Thirteen previously characterized patient-derived tumor xenograft (PDX) models from breast, ovarian, and pancreatic cancer patients harboring germline pathogenic alterations in BRCA1, BRCA2, or PALB2 were used to evaluate the efficacy of AZD5305 alone or in combination with carboplatin or an ataxia telangiectasia and Rad3 related (ATR) inhibitor (ceralasertib) and compared it to the first-generation PARPi olaparib. We performed DNA and RNA sequencing as well as protein-based assays to identify mechanisms of acquired resistance to either PARPi.AZD5305 showed superior antitumor activity than the first-generation PARPi in terms of preclinical complete response rate (75% vs. 37%). The median preclinical progression-free survival was significantly longer in the AZD5305-treated group compared to the olaparib-treated group (> 386 days vs. 90 days). Mechanistically, AZD5305 induced more replication stress and genomic instability than the PARP1/2 inhibitor olaparib in PARPi-sensitive tumors. All tumors at progression with either PARPi (39/39) showed increase of HRR functionality by RAD51 foci formation. The most prevalent resistance mechanisms identified were the acquisition of reversion mutations in BRCA1/BRCA2 and the accumulation of hypomorphic BRCA1. AZD5305 did not sensitize PDXs with acquired resistance to olaparib but elicited profound and durable responses when combined with carboplatin or ceralasertib in 3/6 and 5/5 models, respectively.Collectively, these results show that the novel PARP1 selective inhibitor AZD5305 yields a potent antitumor response in PDX models with HRD and delays PARPi resistance alone or in combination with carboplatin or ceralasertib, which supports its use in the clinic as a new therapeutic option.© 2024. The Author(s).