Abstract
Investigation of novel molecular mechanisms is essential to develop strategies to overcome acquired resistance to EGFR tyrosine kinase inhibitors (TKI). Integrin has been demonstrated as a regulator of cancer progression. The aim of this study was to identify which specific integrins are involved and regulated in acquired resistance to EGFR TKIs in EGFR-mutant lung cancer. The expression levels of integrin subunits were examined in EGFR-mutant lung cancer cells and xenograft tumors with acquired resistance to EGFR TKIs. Manipulation of integrin β3 was performed to explore whether integrin β3 overexpression was associated with TKI resistance, anoikis resistance, EMT, and cancer stemness in resistant lung cancer. To explore the mechanism, TGFβ1 level was examined, and TGFβ1 inhibitor was then used. Integrin β3 was dramatically and consistently overexpressed in acquired gefitinib- or osimertinib-resistant lung cancer in vitro and in vivo Integrin β3 was also involved in the progression of lung adenocarcinoma. Antagonizing integrin β3 increased the TKI sensitivity and delayed the occurrence of TKI resistance in vitro and in vivo, as well as suppressed proliferation, anoikis resistance, and EMT phenotype in lung cancer cells. Overexpression of integrin β3 was also associated with the enhanced cancer stemness that was acquired in the development of resistance and suppressed by antagonizing integrin β3. Mechanistically, integrin β3 was induced by increased TGFβ1 levels in acquired TKI-resistant lung cancer. Our study identified the TGFβ1/integrin β3 axis as a promising target for combination therapy to delay or overcome acquired resistance to EGFR TKIs in EGFR-mutant lung cancer.
Highlights
First-generation EGFR tyrosine kinase inhibitors (TKI), including gefitinib and erlotinib, have demonstrated dramatic efficacy in non–small cell lung cancer (NSCLC) patients with EGFRactivating mutations [1]
Integrin b3 was overexpressed in acquired EGFR TKI-resistant lung cancer cells and tumors
To identify which specific integrins are involved in acquired EGFR TKI resistance in NSCLC, we first generated in vitro models by growing EGFR TKI-sensitive NSCLC cell lines (HCC827 and PC9) in increasing concentrations of an EGFR TKI as we previously reported [12]
Summary
First-generation EGFR tyrosine kinase inhibitors (TKI), including gefitinib and erlotinib, have demonstrated dramatic efficacy in non–small cell lung cancer (NSCLC) patients with EGFRactivating mutations [1]. Despite an impressive initial response, almost all patients eventually have a relapse due to the occurrence of acquired resistance. The secondary EGFR mutation T790M has been reported to be the most common mechanism of acquired resistance to first-generation TKIs [2, 3]. Thirdgeneration TKIs, such as osimertinib, which was approved by the FDA in 2017 for patients with EGFR T790M-positive NSCLC whose disease progressed during or after EGFR TKI therapy, have. Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).
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