Abstract
Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) are widely applied to treat EGFR-mutant non-small cell lung cancer (NSCLC). BIM is a BH3 domain-containing protein encoded by BCL2L11. Some EGFR-mutant NSCLC patients showing BIM deletion polymorphism are resistant to EGFR TKIs. We retrospectively investigated BIM deletion polymorphism in NSCLC patients, its correlation with EGFR TKI (erlotinib) resistance, and the mechanism underlying the drug resistance. Among 245 EGFR-mutant NSCLC patients examined, BIM deletion polymorphism was detected in 43 (12.24%). Median progression-free and overall survival was markedly shorter in patients with BIM deletion polymorphism than with BIM wide-type. Moreover, NSCLC cells expressing EGFR-mutant harboring BIM polymorphism were more resistant to erlotinib-induced apoptosis than BIM wide-type cells. However, combined use of erlotinib and the BH3-mimetic ABT-737 up-regulated BIM expression and overcame erlotinib resistance in EGFR-mutant NSCLC cells harboring BIM deletion polymorphism. In vivo, erlotinib suppressed growth of BIM wide-type NSCLC cell xenographs by inducing apoptosis. Combined with ABT-737, erlotinib also suppressed NSCLC xenographs expressing EGFR-mutant harboring BIM deletion polymorphism. These results indicate that BIM polymorphism is closely related to a poor clinical response to EGFR TKIs in EGFR-mutant NSCLC patients, and that the BH3-mimetic ABT-737 restores BIM functionality and EGFR-TKI sensitivity.
Highlights
The efficiency of cytotoxic chemotherapy among patients with advanced non-small cell lung cancer (NSCLC) is about 30%, and the median survival time is only about 10 months [1, 2]
Among 418 initially eligible patients, 173 patients were excluded, leaving 245 patients for the final analysis (Figure 1). 245 cases NSCLC patients histologically confirmed in our hospital from September 2009 to October 2015 were analyzed by BIM polymorphism analysis
We found that 43 patients (17.6%) have BIM polymorphism
Summary
The efficiency of cytotoxic chemotherapy among patients with advanced non-small cell lung cancer (NSCLC) is about 30%, and the median survival time is only about 10 months [1, 2]. EGFR TKIs perform better than traditional platinum containing chemotherapeutic agents in NSCLC patients containing EGFR mutations, and are considered the first-line therapy [5]. About 25% of EGFR mutant patients exhibit resistance to EGFRTKIs [6]. BIM is the essential protein that promotes cell death [9, 10]. By combining with members of the pro-survival Bcl-2 subfamily, BIM promotes cell apoptosis [11, 12]
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