Ju Lixia, Dong Zhiyi, Yang Juan, Li Minghua
Department of Integrative Medicine, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University, Shanghai 200433, P.R. China.
Department of Emergency, Shanghai Pulmonary Hospital, Tongji University Medical School Cancer Institute, Tongji University, Shanghai 200433, P.R. China.
Oncol Lett. 2020 Dec;20(6):363. doi: 10.3892/ol.2020.12218. Epub 2020 Oct 15.
Although targeted therapy has achieved a great breakthrough in the treatment of lung adenocarcinoma, there are still no effective targeted drugs for lung squamous cell carcinoma (SqCC). In addition, as immunotherapy can only prolong the overall survival (OS) of lung SqCC by ≤5 months, chemotherapy and radiotherapy are still the main types of therapy for advanced SqCC. The expression level of epithelial growth factor receptor (EGFR) in patients with lung SqCC is higher compared with those with adenocarcinoma, but the former group is intrinsically resistant to EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Therefore, if the drug resistance in patients with lung SqCC could be reversed, the majority of patients may benefit from EGFR-TKIs. In the present study, the high-throughput RNA interference technology was used to screen the genes involved in the EGFR-TKI erlotinib resistance of lung SqCCs, and integrin-linked kinase (ILK) was identified to be the most effective. The role of ILK in erlotinib resistance was further studied in cell lines, and the expression of ILK was analyzed in patients with SqCC and adenocarcinoma. Finally, the mechanism of ILK in EGFR-TKIs resistance was analyzed using Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) and ingenuity pathway analysis (IPA). The results demonstrated that the ILK gene knockdown could overcome erlotinib resistance by inhibiting cell proliferation, inducing apoptosis and blocking the cell cycle at the G2/M phase. The expression of ILK in patients with SqCC was significantly higher compared with those with adenocarcinoma with sensitizing EGFR mutations. In addition, the cell cycle pathway 'G2/M DNA damage and checkpoint regulation' was identified to be significantly inhibited by ILK knockdown in IPA, KEGG and GO analysis. The results of the present study may improve the understanding of EGFR-TKI resistance in lung SqCCs, thus promoting the development of potential targeted therapies for lung SqCCs.
尽管靶向治疗在肺腺癌的治疗中取得了重大突破，但肺鳞状细胞癌（SqCC）仍没有有效的靶向药物。此外，由于免疫疗法仅能将肺SqCC的总生存期（OS）延长≤5个月，化疗和放疗仍是晚期SqCC的主要治疗方式。与腺癌患者相比，肺SqCC患者上皮生长因子受体（EGFR）的表达水平更高，但前一组对EGFR-酪氨酸激酶抑制剂（EGFR-TKIs）具有内在抗性。因此，如果能逆转肺SqCC患者的耐药性，大多数患者可能会从EGFR-TKIs中获益。在本研究中，采用高通量RNA干扰技术筛选参与肺SqCC对EGFR-TKI厄洛替尼耐药的基因，并确定整合素连接激酶（ILK）是最有效的。在细胞系中进一步研究了ILK在厄洛替尼耐药中的作用，并分析了SqCC和腺癌患者中ILK的表达。最后，使用京都基因与基因组百科全书（KEGG）、基因本体论（GO）和 Ingenuity 通路分析（IPA）分析了ILK在EGFR-TKIs耐药中的机制。结果表明，ILK基因敲低可通过抑制细胞增殖、诱导细胞凋亡和在G2/M期阻断细胞周期来克服厄洛替尼耐药。与具有敏感EGFR突变的腺癌患者相比，SqCC患者中ILK的表达明显更高。此外，在IPA、KEGG和GO分析中，细胞周期途径“G2/M DNA损伤和检查点调节”被确定为ILK敲低可显著抑制。本研究结果可能会增进对肺SqCC中EGFR-TKI耐药性的理解，从而促进肺SqCC潜在靶向治疗的发展。
