PARP抑制剂使PRMT5失活赋予MTAP缺陷型癌症高易感性
Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers.
摘要(中文译文)
甲基硫代腺苷磷酸化酶（MTAP）因纯合缺失导致的缺陷在实体瘤中普遍存在，并促进恶性进展，从而使癌细胞对蛋白质精氨酸甲基转移酶5（PRMT5）的功能障碍变得敏感。本研究旨在探讨聚（ADP-核糖）聚合酶（PARP）抑制剂是否可通过在MTAP缺陷肿瘤中使PRMT5失活来利用这一脆弱性。在PARP抑制剂处理后，于体外和体内评估了PRMT5活性。在实体瘤模型中，包括体内MTAP缺陷肿瘤模型，评估了PARP抑制剂单药或与MTAP抑制剂MTDIA或PRMT5抑制剂EPZ015666联合使用的抗肿瘤效果。PARP抑制剂在体外和体内均有效使PRMT5失活，并加重了PARP抑制诱导的DNA双链断裂。此外，PARP抑制剂在实体瘤模型中与MTDIA或EPZ015666联合使用时显示出显著的协同效应。MTAP缺陷肿瘤在体内对奥拉帕利表现出更高的敏感性，与单用奥拉帕利相比，奥拉帕利联合MTDIA或EPZ015666治疗产生了更好的治疗效果。这些发现表明，PARP抑制剂通过靶向使PRMT5失活，可作为MTAP缺陷肿瘤的一种潜在治疗策略，并支持在这一分子背景下进一步评估基于PARP抑制剂的联合治疗。
Abstract
Methylthioadenosine phosphorylase (MTAP) deficiency caused by homozygous deletion is prevalent in solid tumors and contributes to malignant progression, thereby rendering cancer cells vulnerable to dysfunction of protein arginine methyltransferase 5 (PRMT5). This study aimed to investigate whether Poly (ADP-ribose) polymerase (PARP) inhibitors could exploit this vulnerability through PRMT5 inactivation in MTAP-deficient tumors. PRMT5 activity was assessed in vitro and in vivo following PARP inhibitor treatment. The antitumor effects of PARP inhibitors alone or in combination with either the MTAP inhibitor MTDIA or the PRMT5 inhibitor EPZ015666 were evaluated in solid tumor models, including MTAP-deficient tumor models in vivo. PARP inhibitors effectively inactivated PRMT5 in vitro and in vivo and exacerbated DNA double-strand breaks induced by PARP inhibition. Moreover, PARP inhibitors showed significant synergistic effects when combined with either MTDIA or EPZ015666 in solid tumor models. MTAP-deficient tumors exhibited increased vulnerability to olaparib in vivo, and combined treatment with olaparib plus MTDIA or EPZ015666 produced improved therapeutic outcomes compared with olaparib alone. These findings identify PARP inhibitors as a potential therapeutic strategy for MTAP-deficient tumors through targeted inactivation of PRMT5 and support further evaluation of PARP inhibitor-based combination therapies in this molecular context.
如何引用
AMA
Qi Liu, Yuling Sheng, Folan Lin, Haoyuan Tan, Yanyun Chang, Xiaopeng Lu, et al. Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers.. Cancers. 2026; doi:10.3390/cancers18091335.
APA
Qi Liu, Yuling Sheng, Folan Lin, Haoyuan Tan, Yanyun Chang, Xiaopeng Lu, et al (2026). Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers.. Cancers. https://doi.org/10.3390/cancers18091335
GB/T 7714
Qi Liu, Yuling Sheng, Folan Lin, Haoyuan Tan, Yanyun Chang, Xiaopeng Lu, et al. Inactivation of PRMT5 by PARP Inhibitors Confers High Susceptibility in MTAP-Deficient Cancers.[J]. Cancers, 2026 doi:10.3390/cancers18091335.
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