Yan Rui, Fan Xiaona, Xiao Zeru, Liu Heshu, Huang Xuying, Liu Jian, Zhang Shucai, Yao Jiannan, An Guangyu, Ge Yang
Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, Beijing, 100020, China.
Beijing Chao-Yang Hospital Department of Oncology, Capital Medical University, Beijing, 100020, China; Medical Research Center, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, 100020, China.
Cancer Lett. 2022 Apr 10;531:83-97. doi: 10.1016/j.canlet.2022.01.030. Epub 2022 Feb 11.
Lung adenocarcinoma is the most common form of lung cancer, accounting for 60% of non-small cell lung cancer (NSCLC) cases in Asian patients. Importantly, nearly half of these patients have epithelial growth factor receptor (EGFR) mutations. Though EGFR-tyrosine kinase inhibitors (EGFR-TKIs) are recommended as the first-line therapy for NSCLC patients, the development of resistance reduces their efficiency and limits their application. As the complicated and heterogeneous mechanism of acquired resistance among individuals, the efficiency of anti-angiogenesis therapy, immune checkpoint inhibitors, or chemo-radiotherapies is rather less promising. In this research, we investigated the role of the tumor stem cell marker DCLK1 in EGFR-TKI resistance of lung adenocarcinoma. We discovered that DCLK1 was critical in maintaining the stemness of tumor cells through the Wnt/β-Catenin pathway, which was conducive to the development of EGFR-TKI resistance. Inhibiting DCLK1 activity restored the sensitivity of TKI-resistant tumor cells and organoids. Moreover, our study showed that DCLK1 inhibitor had a synergistic effect in controlling tumor growth when combined with EGFR-TKIs. Overall, our study provides new insights into EGFR-TKI resistant lung adenocarcinoma through inhibition of DCLK1 expression.
肺腺癌是肺癌最常见的类型，在亚洲患者的非小细胞肺癌（NSCLC）病例中占60%。重要的是，这些患者中近一半存在表皮生长因子受体（EGFR）突变。尽管EGFR酪氨酸激酶抑制剂（EGFR-TKIs）被推荐作为NSCLC患者的一线治疗药物，但耐药性的产生降低了它们的疗效并限制了其应用。由于个体获得性耐药的机制复杂且具有异质性，抗血管生成疗法、免疫检查点抑制剂或放化疗的疗效相当有限。在本研究中，我们调查了肿瘤干细胞标志物双皮质素样激酶1（DCLK1）在肺腺癌EGFR-TKI耐药中的作用。我们发现DCLK1通过Wnt/β-连环蛋白信号通路对维持肿瘤细胞的干性至关重要，这有利于EGFR-TKI耐药性的发展。抑制DCLK1活性可恢复TKI耐药肿瘤细胞和类器官的敏感性。此外，我们的研究表明，DCLK1抑制剂与EGFR-TKIs联合使用时在控制肿瘤生长方面具有协同作用。总体而言，我们的研究通过抑制DCLK1表达为EGFR-TKI耐药的肺腺癌提供了新的见解。
