异常激活的 OPN/整合素 αVβ3/FAK 信号通路导致 EGFR 突变型非小细胞肺癌对 EGFR-TKI 耐药。

Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer.

机构信息

Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Soochow University, Suzhou, 215006, People's Republic of China.

Institute of Respiratory Diseases, Soochow University, Suzhou, 215006, People's Republic of China.

出版信息

J Hematol Oncol. 2020 Dec 7;13(1):169. doi: 10.1186/s13045-020-01009-7.

BACKGROUND

Acquired epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance limits the long-term clinical efficacy of tyrosine kinase-targeting drugs. Although most of the mechanisms of acquired EGFR-TKI resistance have been revealed, the mechanism of ~ 15% of cases has not yet been elucidated.

METHODS

Cell viability was analysed using the Cell Counting Kit-8 (CCK-8) assay. Proteome profiler array analysis was performed to find proteins contributing to acquired EGFR-TKI resistance. Secreted OPN was detected by ELISA. Immunohistochemical analysis was conducted to detect expression of integrin αV in NSCLC tissue. The effect of VS-6063 on apoptosis and proliferation of PC9 gefitinib-resistant cells was detected by fluorescence-activated cell sorting (FACS) and clonogenic assays. A mouse xenograft model was used to assess the effect of VS-6063 on the sensitivity of PC9 gefitinib-resistant cells to gefitinib.

RESULTS

OPN was overexpressed in acquired EGFR-TKI-resistant NSCLCs. Secreted OPN contributed to acquired EGFR-TKI resistance by activating the integrin αVβ3/FAK pathway. Inhibition of FAK signalling increased sensitivity to EGFR-TKIs in PC9 gefitinib-resistant cells both in vitro and in vivo.

CONCLUSIONS

OPN contributes to acquired EGFR-TKI resistance by up-regulating expression of integrin αVβ3, which activates the downstream FAK/AKT and ERK signalling pathways to promote cell proliferation in NSCLC.

背景

获得性表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI）耐药限制了酪氨酸激酶靶向药物的长期临床疗效。尽管已经揭示了大多数获得性 EGFR-TKI 耐药的机制，但仍有大约 15%的病例的机制尚未阐明。

方法

使用细胞计数试剂盒-8（CCK-8）测定法分析细胞活力。进行蛋白质组谱分析以寻找导致获得性 EGFR-TKI 耐药的蛋白质。通过 ELISA 检测分泌的 OPN。通过免疫组织化学分析检测非小细胞肺癌组织中整合素 αV 的表达。通过荧光激活细胞分选（FACS）和集落形成测定法检测 VS-6063 对 PC9 吉非替尼耐药细胞凋亡和增殖的影响。使用小鼠异种移植模型评估 VS-6063 对 PC9 吉非替尼耐药细胞对吉非替尼敏感性的影响。