一种新型布鲁顿酪氨酸激酶抑制剂通过ATF3诱导铁死亡抑制胰腺神经内分泌肿瘤进展

Abstract

Simple SummaryTherapeutic options for pancreatic neuroendocrine neoplasms (pNENs) remain limited, making the development of novel agents of great importance. Bruton’s tyrosine kinase inhibitors (BTKis) have shown promising therapeutic potential in solid tumors; however, ibrutinib demonstrates poor efficacy against neuroendocrine neoplasms. In this study, we synthesized a novel pyrrolopyrimidine-based BTKi, QY21, and demonstrated that QY21 significantly suppressed the proliferation of pNENs both in vitro and in vivo. Mechanistically, QY21 markedly upregulated ATF3 expression in pNENs, inducing the accumulation of reactive oxygen species and lipid peroxidation. Genetic knockdown of ATF3 or administration of the ferroptosis inhibitor ferrostatin-1 significantly attenuated the anti-proliferative capacity of QY21. In summary, our study characterized a novel BTKi, QY21, which suppresses pNENs proliferation by triggering ATF3-mediated ferroptosis. These findings may provide a potential therapeutic strategy for pNENs.Objective:Current therapeutic regimens for pancreatic neuroendocrine neoplasms (pNENs) remain limited and fail to yield notable improvements in overall survival. Therefore, the development of novel agents is of paramount importance. Bruton’s tyrosine kinase inhibitors (BTKis) have demonstrated promising therapeutic potential in solid tumors; however, ibrutinib, a classic BTKi, exhibits unsatisfactory clinical efficacy against pNENs. In this study, we synthesized a novel pyrrolopyrimidine-based BTKi, QY21, and aimed to investigate its inhibitory effects on pNEN cell proliferation both in vitro and vivo and identify the core signaling pathways mediating its suppressive effects on pNENs.Methods:CCK-8, EdU, and colony formation assays were conducted to assess the effect of QY21 on pNENs in vitro. Transcriptome sequencing, quantitative real-time PCR, Western blotting, and flow cytometry were employed to explore the mechanisms. A xenograft tumor model in nude mice w