P21-activated kinase 2-mediated β-catenin signaling promotes cancer stemness and osimertinib resistance in EGFR-mutant non-small-cell lung cancer
P21-activated kinase 2-mediated β-catenin signaling promotes cancer stemness and osimertinib resistance in EGFR-mutant non-small-cell lung cancer
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DOI：
10.1038/s41388-022-02438-z
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发表时间：
2022-08
期刊：
影响因子：
8
通讯作者：
Yanmei Yi;Pan Li;Yuanfeng Huang;Danyang Chen;Siwen Fan;Jun Wang;Mi Yang;Shanshan Zeng;J. Deng;Xinwu Lv;Kai-jun Luo;Zhiwei He;H. Liu
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作者：
Yanmei Yi;Pan Li;Yuanfeng Huang;Danyang Chen;Siwen Fan;Jun Wang;Mi Yang;Shanshan Zeng;J. Deng;Xinwu Lv;Kai-jun Luo;Zhiwei He;H. Liu
Osimertinib(AZD9291)是第三代表皮生长因子受体(EGFR)酪氨酸激酶抑制剂(TKI)，用于治疗携带EGFR激活突变或耐药T790M突变的晚期非小细胞肺癌(NSCLC)患者。然而，在EGFR突变的NSCLC中，对奥西美替尼的获得性耐药性是不可避免的。通过基于全球质谱学的磷酸化蛋白质组学方法，我们发现激活的p21-激活的蛋白激酶2(PAK2)/β-连环素轴是奥西美替尼耐药的驱动因素。我们发现，PAK2直接磷酸化β-连环蛋白，增加β-连环蛋白的核定位，导致β-连环蛋白表达和转录活性增加，进而增强肿瘤干细胞样特性和奥西美替尼的耐药性。此外，我们还发现，HER3作为PAK2的上游调节因子，在奥西美替尼耐药细胞中驱动PAK2/β-连环蛋白通路的激活。通过检查EGFR突变的非小细胞肺癌患者的组织标本，进一步证实了这些发现的临床相关性。结果表明，经奥西美替尼治疗后复发的突变型非小细胞肺癌患者组织中HER3、p-PAK2和β-catenin的水平较相应的未治疗组织升高。此外，在接受EGFR-TKI治疗的非小细胞肺癌患者中，HER3、p-PAK2和β-连环蛋白的高水平与较短的无进展生存期(PFS)相关。此外，我们还观察到，通过敲除PAK2或通过PAK抑制剂的药物靶向抑制PAK2，在体外和体内都显著恢复了奥西美替尼耐药非小细胞肺癌细胞对奥西美替尼的反应。综上所述，PAK_2介导的β-连环蛋白活化在奥西美替尼耐药中起重要作用，靶向HER3/PAK_2/β-连环蛋白通路在获得性耐药非小细胞肺癌中具有潜在的治疗价值。
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), used for treating patients with advanced non-small-cell lung cancer (NSCLC) harboring EGFR-activating mutations or the resistant T790M mutation. However, acquired resistance to osimertinib is inevitable in EGFR-mutant NSCLC. By employing a global mass spectrometry-based phosphoproteomics approach, we identified that the activated p21-activated kinase 2 (PAK2)/β-catenin axis acts as a driver of osimertinib resistance. We found that PAK2 directly phosphorylates β-catenin and increases the nuclear localization of β-catenin, leading to the increased expression and transcriptional activity of β-catenin, which in turn enhances cancer stem-like properties and osimertinib resistance. Moreover, we revealed that HER3 as an upstream regulator of PAK2, drives the activation of PAK2/β-catenin pathways in osimertinib-resistant cells. The clinical relevance of these findings was further confirmed by examining tissue specimens from patients with EGFR-mutant NSCLC. The results demonstrated that the levels of HER3, phospho-PAK2 (p-PAK2) and β-catenin in the tissues from patients with EGFR-mutant NSCLC, that had relapsed after treatment with osimertinib, were elevated compared to those of the corresponding untreated tissues. Additionally, the high levels of HER3, p-PAK2 and β-catenin correlated with shorter progression-free survival (PFS) in patients with EGFR-TKI-treated NSCLC. We additionally observed that the suppression of PAK2 via knockdown or pharmacological targeting with PAK inhibitors markedly restored the response of osimertinib-resistant NSCLC cells to osimertinib both in vitro and in vivo. In conclusion, these results indicated that the PAK2-mediated activation of β-catenin is important for osimertinib resistance and targeting the HER3/PAK2/β-catenin pathway has potential therapeutic value in NSCLCs with acquired resistance to osimertinib.