Yang Zheng, Chan Kin Iong, Kwok Hang Fai, Tam Kin Yip
Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China.
Centre for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Avenida de Universidade, Taipa, Macau SAR, PR China; Department of Pathology, Kiang Wu Hospital, Macau SAR, PR China.
Transl Oncol. 2019 Nov;12(11):1516-1524. doi: 10.1016/j.tranon.2019.08.003. Epub 2019 Aug 23.
Epidermal growth factor receptor (EGFR) mutations were found in 30%-40% of non-small cell lung cancer (NSCLC) patients, who often responded well to EGFR tyrosine kinase inhibitors (EGFR-TKIs) as exemplified by erlotinib and gefitinib in the past decades. However, EGFR mutation-led drug resistance usually occurred upon prolonged treatment with EGFR-TKI. Herein, we study the anticancer effects of EGFR-TKI in combination with a newly developed antibody, A9(B8), to target a disintegrin and metalloprotease (ADAM) 17 that was overexpressed in NSCLC patients. NSCLC cell lines with different EGFR mutations were used to evaluate the drug combination. We have found that the EGFR-TKI-A9(B8) combination exhibited enhanced anticancer effects in NCI-H1975 cells harboring L858R and T790M mutations, which were due to simultaneous suppression of extracellular signal-regulated kinases phosphorylation. Our results suggested that targeting ADAM17 could potentiate the anticancer effects of EGFR-TKI against NSCLC and overcome drug resistance due to EGFR mutations.
在30%-40%的非小细胞肺癌（NSCLC）患者中发现了表皮生长因子受体（EGFR）突变，在过去几十年中，这些患者通常对EGFR酪氨酸激酶抑制剂（EGFR-TKIs）反应良好，如厄洛替尼和吉非替尼。然而，EGFR突变导致的耐药性通常在长期使用EGFR-TKI治疗后出现。在此，我们研究了EGFR-TKI与一种新开发的抗体A9（B8）联合使用的抗癌效果，该抗体靶向在NSCLC患者中过度表达的去整合素和金属蛋白酶（ADAM）17。使用具有不同EGFR突变的NSCLC细胞系来评估药物组合。我们发现，EGFR-TKI-A9（B8）组合在携带L858R和T790M突变的NCI-H1975细胞中表现出增强的抗癌效果，这是由于细胞外信号调节激酶磷酸化的同时受到抑制。我们的结果表明，靶向ADAM17可以增强EGFR-TKI对NSCLC的抗癌效果，并克服由EGFR突变引起的耐药性。
