Neuroendocrine neoplasms (NENs) represent a rare and heterogeneous group of malignancies, sharing features of both neural and endocrine cells. NENs G3 appear as a highly aggressive subset with a poor prognosis and limited therapeutic options. The small-molecule inhibitor of the WEE1 tyrosine kinase, adavosertib (AZD1775), has previously demonstrated potent anti-tumor effects on various types of cancer in preclinical and clinical studies. However, the role of adavosertib in NENs G3 had remained elusive. We evaluated the effects of adavosertib on pancreatic (BON-1, QGP-1) and bronchopulmonary (NCI-H720) neuroendocrine tumor cell lines applying 2D and 3D spheroid models. We newly demonstrated that adavosertib is sufficient to reduce cell viability and proliferation in neuroendocrine cell lines with features of high-grade NENs. As underlying mechanisms, we identified adavosertib-mediated DNA double-strand breaks and a G2/M cell cycle checkpoint abrogation leading into mitotic catastrophe and cancer cell apoptosis. Silencing of WEE1 via siRNA transfection resulted in a phenotype similar to adavosertib treatment. Together, inhibition of the WEE1 tyrosine kinase applying adavosertib on NENs G3 outlines a promising novel therapeutic strategy.

中文翻译：

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靶向抑制 WEE1 激酶作为神经内分泌肿瘤的新治疗策略。

神经内分泌肿瘤 (NEN) 是一组罕见的异质性恶性肿瘤，具有神经细胞和内分泌细胞的共同特征。NENs G3 似乎是一个高度侵袭性的亚群，预后不良，治疗选择有限。WEE1 酪氨酸激酶的小分子抑制剂 adavosertib (AZD1775) 此前已在临床前和临床研究中证明对各种类型的癌症具有有效的抗肿瘤作用。然而，adavosertib 在 NENs G3 中的作用仍然难以捉摸。我们应用 2D 和 3D 球体模型评估了 adavosertib 对胰腺（BON-1、QGP-1）和支气管肺（NCI-H720）神经内分泌肿瘤细胞系的影响。我们新证明，adavosertib 足以降低具有高级 NEN 特征的神经内分泌细胞系中的细胞活力和增殖。作为潜在机制，我们确定了 adavosertib 介导的 DNA 双链断裂和 G2/M 细胞周期检查点取消导致有丝分裂灾难和癌细胞凋亡。通过 siRNA 转染对 WEE1 进行沉默导致了与 adavosertib 处理相似的表型。总之，在 NEN G3 上应用 adavosertib 抑制 WEE1 酪氨酸激酶概述了一种有前途的新治疗策略。