Yao Zehui, Zhang Huihui, Huang Kewei, Huang Guizhong, Xi Pu, Jiang Lingmin, Qin Dailei, Chen Fan, Li Shengping, Wei Ran
State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, 510060, China.
Center for Orthopaedic Surgery, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510060, China.
Transl Oncol. 2025 Jan;51:102206. doi: 10.1016/j.tranon.2024.102206. Epub 2024 Nov 27.
While poly (adenosine diphosphate-ribose) polymerase inhibitors (PARPi) have achieved specific clinical benefits in a subset of pancreatic ductal adenocarcinoma (PDAC) patients, the potential role of the PARPi niraparib in PDAC necessitates further exploration. In this study, we demonstrated that Niraparib exhibited a pronounced inhibitory effect on autophagy in PDAC both in vitro and in vivo. Mechanistically, this inhibition was primarily attributed to niraparib's ability to disrupt the fusion process between autophagosomes and lysosomes, while potentially exerting a relatively minor impact on the initial stage of autophagy. The blockade effect observed may be mediated via modulation of the ERK signaling pathway, and this effect can be mitigated by the application of an ERK inhibitor (FR180204). Notably, the combined treatment regimen of niraparib and gemcitabine failed to elicit the anticipated synergistic effects in wild-type PANC-1 cells, instead exhibiting pronounced antagonistic interactions. However, in gemcitabine-resistant PANC-1 cells, the combination of niraparib and gemcitabine exhibited modest additive effects. Furthermore, niraparib demonstrated a heightened cytotoxic potency against gemcitabine-resistant PANC-1 cells compared to wild-type PANC-1 cells, both in vitro and in vivo. Our research established that niraparib inhibits late-stage autophagy in PDAC, potentially representing a valuable salvage therapy for gemcitabine-resistant PDAC. Further clinical studies are justified.
虽然聚（二磷酸腺苷-核糖）聚合酶抑制剂（PARPi）在一部分胰腺导管腺癌（PDAC）患者中取得了特定的临床益处，但PARPi尼拉帕利在PDAC中的潜在作用仍需进一步探索。在本研究中，我们证明尼拉帕利在体外和体内对PDAC的自噬均表现出显著的抑制作用。从机制上讲，这种抑制主要归因于尼拉帕利破坏自噬体与溶酶体之间融合过程的能力，而对自噬的初始阶段可能产生相对较小的影响。观察到的阻断作用可能是通过调节ERK信号通路介导的，并且这种作用可以通过应用ERK抑制剂（FR180204）来减轻。值得注意的是，尼拉帕利与吉西他滨的联合治疗方案在野生型PANC-1细胞中未能引发预期的协同作用，反而表现出明显的拮抗相互作用。然而，在吉西他滨耐药的PANC-1细胞中，尼拉帕利与吉西他滨的联合表现出适度的相加作用。此外，与野生型PANC-1细胞相比，尼拉帕利在体外和体内对吉西他滨耐药的PANC-1细胞均表现出更高的细胞毒性效力。我们的研究表明，尼拉帕利抑制PDAC的晚期自噬，可能是吉西他滨耐药PDAC的一种有价值的挽救疗法。进一步的临床研究是有必要的。
