Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer.
Abnormally activated OPN/integrin αVβ3/FAK signalling is responsible for EGFR-TKI resistance in EGFR mutant non-small-cell lung cancer.
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DOI：
10.1186/s13045-020-01009-7
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发表时间：
2020-12-07
影响因子：
28.5
通讯作者：
Huang JA
中科院分区：
文献类型：
--
作者：
Fu Y;Zhang Y;Lei Z;Liu T;Cai T;Wang A;Du W;Zeng Y;Zhu J;Liu Z;Huang JA
获得的表皮生长因子受体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。尽管已经揭示了获得的EGFR-TKI耐药性的大多数机制，但尚未阐明约15％的病例的机制。使用细胞计数KIT-8（CCK-8）测定法分析细胞活力。进行了蛋白质组剖面阵列分析，以发现有助于获得的EGFR-TKI抗性的蛋白质。 Elisa检测到了分泌的OPN。进行了免疫组织化学分析以检测NSCLC组织中整联蛋白αV的表达。 VS-6063对PC9吉非替尼细胞的凋亡和增殖的影响通过荧光激活的细胞分选（FACS）和克隆发生测定来检测。使用小鼠异种移植模型来评估VS-6063对PC9吉非替尼对吉非替尼的敏感性的影响。 OPN在获得的EGFR-TKI耐药NSCLC中过表达。分泌的OPN通过激活整合蛋白αVβ3/FAK途径，导致获得的EGFR-TKI抗性。 FAK信号传导的抑制增加了对PC9 Gefitinib耐药细胞在体外和体内的敏感性。 OPN通过上调整联蛋白αVβ3的表达有助于获得的EGFR-TKI抗性，该表达激活了下游FAK/AKT和ERK信号传导途径，以促进NSCLC中的细胞增殖。
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. 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. 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. 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.
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影响因子：
5.2
作者：
Nieberler M;Reuning U;Reichart F;Notni J;Wester HJ;Schwaiger M;Weinmüller M;Räder A;Steiger K;Kessler H
通讯作者：
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影响因子：
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影响因子：
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作者：
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通讯作者：
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