Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan.
Nano Life Science Institute, Kanazawa University, Kanazawa, Japan.
Cancer Sci. 2020 Jul;111(7):2374-2384. doi: 10.1111/cas.14454. Epub 2020 Jun 11.
A novel epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, osimertinib, has marked efficacy in patients with EGFR-mutant lung cancer. While epithelial-mesenchymal transition (EMT) plays a role in the resistance to various targeted drugs, its involvement in EGFR-inhibitor resistance remains largely unknown. Preclinical experiments with osimertinib-resistant lung cancer cells showed that EMT was associated with decreased microRNA-200c and increased ZEB1 expression. In several resistant clone cells, pretreatment with the histone deacetylase inhibitor quisinostat helped overcome the resistance by reverting EMT. Furthermore, drug screening from a library of 100 kinase inhibitors indicated that Glycogen synthase kinase-3 (GSK-3) inhibitors, such as LY2090314, markedly inhibited the growth and induced apoptosis of resistant cells, specifically those with a mesenchymal phenotype. These results suggest that GSK-3 inhibition could be useful to circumvent EMT-associated resistance to osimertinib in EGFR-mutant lung cancer.
一种新型表皮生长因子受体（EGFR）-酪氨酸激酶抑制剂奥希替尼在 EGFR 突变型肺癌患者中具有显著疗效。虽然上皮-间充质转化（EMT）在各种靶向药物的耐药性中起作用，但它在 EGFR 抑制剂耐药性中的作用在很大程度上尚不清楚。奥希替尼耐药性肺癌细胞的临床前实验表明，EMT 与 microRNA-200c 的减少和 ZEB1 表达的增加有关。在几个耐药克隆细胞中，组蛋白去乙酰化酶抑制剂 quisinostat 的预处理通过逆转 EMT 有助于克服耐药性。此外，从 100 种激酶抑制剂文库中进行的药物筛选表明，糖原合酶激酶-3（GSK-3）抑制剂，如 LY2090314，可显著抑制耐药细胞的生长并诱导其凋亡，特别是那些具有间充质表型的细胞。这些结果表明，GSK-3 抑制可能有助于克服 EGFR 突变型肺癌中奥希替尼相关的 EMT 耐药性。
