Li Min, Chen Hongling, Sun Tong, Ma Zhuo, Chen Xi, Wu Dandan, Huang Wenbin, Wang Xuerong
Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China, 210029.
Key Laboratory of Human Functional Genomics of Jiangsu Province, Nanjing Medical University, Nanjing, Jiangsu Province, People's Republic of China, 210029.
Onco Targets Ther. 2020 Jun 9;13:5257-5270. doi: 10.2147/OTT.S249695. eCollection 2020.
Lung cancer is the leading cause of cancer-related deaths. EGFR tyrosine kinase inhibitors, such as erlotinib, were approved for non-small cell lung carcinoma patients with EGFR mutations. However, the acquired resistance of these inhibitors has not been fully clarified. Therefore, clarifying the mechanism and developing new rationales to overcome the drug resistance are urgently needed.
A pair of erlotinib sensitive and resistant cells was used to identify the key molecules in mediating erlotinib resistance. Loss- or gain-of-function study was used to confirm the effects of the key molecules. Xenograft mouse model and human cancer tissue sample studies were conducted for further corroboration.
HCC827 cells with acquired resistance to erlotinib underwent epithelial-mesenchymal transition and exhibited enhanced p70S6K signaling compared to parental sensitive cells. Moreover, in erlotinib resistant cells, downregulation of p70S6K expression using either siRNA or shRNA reversed EMT and partially overcame erlotinib resistance. Meanwhile, in erlotinib sensitive cells, overexpression of p70S6K promoted EMT and induced erlotinib resistance. Upregulation of p70S6K signaling in erlotinib resistant cells was caused by reduced GSK3β-mediated protein degradation of mTOR and raptor. Additionally, p70S6K silencing suppressed the growth of erlotinib resistant cells in a xenograft mouse model. Finally, we found a correlation between p70S6K and E-cadherin expression in human non-small-cell lung cancer (NSCLC) tissue samples.
Our findings suggest that p70S6K-induced EMT plays an important role in the acquired resistance of erlotinib and provides a novel therapeutic rationale of targeting p70S6K in NSCLC therapy.
肺癌是癌症相关死亡的主要原因。表皮生长因子受体（EGFR）酪氨酸激酶抑制剂，如厄洛替尼，已被批准用于治疗具有EGFR突变的非小细胞肺癌患者。然而，这些抑制剂的获得性耐药机制尚未完全阐明。因此，迫切需要阐明其机制并开发新的策略来克服耐药性。
使用一对对厄洛替尼敏感和耐药的细胞来鉴定介导厄洛替尼耐药的关键分子。通过功能缺失或功能获得研究来确认关键分子的作用。进行异种移植小鼠模型和人类癌症组织样本研究以进一步证实。
与亲本敏感细胞相比，对厄洛替尼产生获得性耐药的HCC827细胞发生了上皮-间质转化，并表现出增强的p70S6K信号传导。此外，在厄洛替尼耐药细胞中，使用siRNA或shRNA下调p70S6K表达可逆转上皮-间质转化并部分克服厄洛替尼耐药性。同时，在厄洛替尼敏感细胞中，p70S6K的过表达促进上皮-间质转化并诱导厄洛替尼耐药性。厄洛替尼耐药细胞中p70S6K信号传导的上调是由于GSK3β介导的mTOR和raptor蛋白降解减少所致。此外，p70S6K沉默抑制了异种移植小鼠模型中厄洛替尼耐药细胞的生长。最后，我们在人类非小细胞肺癌（NSCLC）组织样本中发现了p70S6K与E-钙粘蛋白表达之间的相关性。
我们的研究结果表明，p70S6K诱导的上皮-间质转化在厄洛替尼的获得性耐药中起重要作用，并为非小细胞肺癌治疗中靶向p70S6K提供了新的治疗策略。
