PIM1 激酶通过调节 EGFR 突变非小细胞肺癌中的 GSK3β 信号通路促进 EMT 相关的奥希替尼耐药。
PIM1 kinase promotes EMT-associated osimertinib resistance via regulating GSK3β signaling pathway in EGFR-mutant non-small cell lung cancer.
发表日期：2024 Sep 03
作者：
Jing Zhou, Xinyue Wang, Zhaona Li, Fan Wang, Lianjing Cao, Xiuqiong Chen, Dingzhi Huang, Richeng Jiang
来源：
Cell Death & Disease
摘要：
在用奥希替尼治疗非小细胞肺癌（NSCLC）时，获得性耐药是不可避免的，造成这种耐药的主要机制之一是上皮间质转化（EMT）。我们确定莫洛尼鼠白血病病毒 1 (PIM1) 前病毒整合位点的上调和糖原合成酶激酶 3β (GSK3β) 的功能失活是 EMT 相关奥希替尼耐药的驱动因素。 PIM1的上调促进奥希替尼耐药细胞的生长、侵袭和耐药，并与EMT分子表达显着相关。从功能上来说，PIM1 通过磷酸化使 GSK3β 失活，从而抑制 snail 家族转录抑制蛋白 1 (SNAIL) 和 snail 家族转录抑制蛋白 2 (SLUG) 的泛素蛋白酶体降解。 SNAIL 和 SLUG 的稳定性和积累促进 EMT 并促进奥希替尼耐药。此外，使用 PIM1 抑制剂治疗可防止 EMT 进展并使奥希替尼耐药 NSCLC 细胞对奥希替尼重新敏感。 PIM1/GSK3β 信号在奥希替尼耐药 NSCLC 的临床样本中被激活，双重表皮生长因子受体 (EGFR)/PIM1 阻断可在体内协同逆转奥希替尼耐药 NSCLC。这些数据确定 PIM1 是 EMT 相关奥希替尼耐药 NSCLC 细胞的驱动因素，并预测 PIM1 抑制剂和奥希替尼联合疗法将为 EGFR 突变 NSCLC 患者提供临床益处。© 2024。作者。
Acquired resistance is inevitable in the treatment of non-small cell lung cancer (NSCLC) with osimertinib, and one of the primary mechanisms responsible for this resistance is the epithelial-mesenchymal transition (EMT). We identify upregulation of the proviral integration site for Moloney murine leukemia virus 1 (PIM1) and functional inactivation of glycogen synthase kinase 3β (GSK3β) as drivers of EMT-associated osimertinib resistance. Upregulation of PIM1 promotes the growth, invasion, and resistance of osimertinib-resistant cells and is significantly correlated with EMT molecules expression. Functionally, PIM1 suppresses the ubiquitin-proteasome degradation of snail family transcriptional repressor 1 (SNAIL) and snail family transcriptional repressor 2 (SLUG) by deactivating GSK3β through phosphorylation. The stability and accumulation of SNAIL and SLUG facilitate EMT and encourage osimertinib resistance. Furthermore, treatment with PIM1 inhibitors prevents EMT progression and re-sensitizes osimertinib-resistant NSCLC cells to osimertinib. PIM1/GSK3β signaling is activated in clinical samples of osimertinib-resistant NSCLC, and dual epidermal growth factor receptor (EGFR)/PIM1 blockade synergistically reverse osimertinib-resistant NSCLC in vivo. These data identify PIM1 as a driver of EMT-associated osimertinib-resistant NSCLC cells and predict that PIM1 inhibitors and osimertinib combination therapy will provide clinical benefit in patients with EGFR-mutant NSCLC.© 2024. The Author(s).