小细胞肺癌（SCLC）患者迫切需要更有效的治疗选择。 SCLC 细胞中 G1 检查点的频繁破坏会产生对 G2/M 检查点的依赖来维持基因组完整性。事实上，在临床前模型中，抑制 G2/M 检查点激酶 WEE1 显示出抑制 SCLC 生长的希望。然而，毒性和获得性耐药性限制了该策略的临床有效性。在这里，我们利用体外和体内 CRISPR-Cas9 敲除筛选，确定了影响 SCLC 细胞对 WEE1 激酶抑制剂 AZD1775 反应的多种因素，包括 GCN2 激酶及其信号通路的其他成员。 AZD1775 治疗后 GCN2 的快速激活会触发 SCLC 细胞的应激反应。 GCN2 通路的药理学或基因激活可增强 AZD1775 杀死癌细胞的能力。因此，GCN2 通路的激活是提高 SCLC 中 WEE1 抑制剂疗效的一种有前景的策略。版权所有 © 2024 作者。由爱思唯尔公司出版。保留所有权利。

Patients with small-cell lung cancer (SCLC) are in dire need of more effective therapeutic options. Frequent disruption of the G1 checkpoint in SCLC cells creates a dependency on the G2/M checkpoint to maintain genomic integrity. Indeed, in pre-clinical models, inhibiting the G2/M checkpoint kinase WEE1 shows promise in inhibiting SCLC growth. However, toxicity and acquired resistance limit the clinical effectiveness of this strategy. Here, using CRISPR-Cas9 knockout screens in vitro and in vivo, we identified multiple factors influencing the response of SCLC cells to the WEE1 kinase inhibitor AZD1775, including the GCN2 kinase and other members of its signaling pathway. Rapid activation of GCN2 upon AZD1775 treatment triggers a stress response in SCLC cells. Pharmacological or genetic activation of the GCN2 pathway enhances cancer cell killing by AZD1775. Thus, activation of the GCN2 pathway represents a promising strategy to increase the efficacy of WEE1 inhibitors in SCLC.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.