Abstract
Loss of PTEN was recently shown to contribute to resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in EGFR mutation-positive non-small cell lung cancer (NSCLC) through activation of the protein kinase AKT. We previously showed that downregulation of the expression of the antiapoptotic protein survivin by EGFR-TKIs contributes to EGFR-TKI-induced apoptosis in EGFR mutation-positive NSCLC cells. We have now investigated the role of survivin expression in EGFR-TKI resistance induced by PTEN loss. The EGFR-TKI erlotinib did not affect survivin expression or induce apoptosis in EGFR mutation-positive NSCLC cells with PTEN loss. Downregulation of survivin either by transfection with a specific short interfering RNA or by exposure to the small-molecule survivin suppressor YM155 reversed erlotinib resistance in such cells in vitro. Furthermore, combination therapy with YM155 and erlotinib inhibited the growth of tumors formed by EGFR mutation-positive, PTEN-deficient NSCLC cells in nude mice to a greater extent than did treatment with either drug alone. These results thus indicate that persistent activation of signaling by the AKT-survivin pathway induced by PTEN loss underlies a mechanism of resistance to erlotinib-induced apoptosis in EGFR mutation-positive NSCLC. They further suggest that the targeting of survivin has the potential to overcome EGFR-TKI resistance in EGFR mutation-positive NSCLC.
Highlights
70% of individuals with non–small cell lung cancer (NSCLC) who harbor somatic mutations in exons of the epidermal growth factor receptor (EGFR) gene that encode the tyrosine kinase domain of the receptor experience substantial tumor regression when treated with the EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib [1]
We recently found that EGFR–TKIs downregulate survivin expression through inhibition of the phosphoinositide 3-kinase (PI3K)–AKT signaling pathway and that such downregulation of survivin contributed to EGFR–TKI-induced apoptosis in EGFR mutation–positive NSCLC cells [13]
To investigate further the contribution of persistent survivin expression to erlotinib resistance associated with PTEN loss, we examined the effect of short interfering RNAs (siRNA)-mediated depletion of survivin on erlotinib-induced apoptosis in parental PC9 cells and the EGFR–TKI-resistant sublines PC9/GEF1-1 and PC9/GEF2-1
Summary
70% of individuals with non–small cell lung cancer (NSCLC) who harbor somatic mutations in exons of the epidermal growth factor receptor (EGFR) gene that encode the tyrosine kinase domain of the receptor experience substantial tumor regression when treated with the EGFR tyrosine kinase inhibitors (TKI) gefitinib or erlotinib [1]. Most patients, even those who show a marked response to initial treatment, develop acquired resistance to EGFR–TKIs after varying periods of time [2]. Several major mechanisms of such acquired resistance, including secondary mutation of EGFR, amplification of MET, and overexpression of hepatocyte growth factor, have been identified, and the development of pharmaceutical agents that target these. Some patients are intrinsically resistant to EGFR–TKIs, even though their tumors harbor activating mutations of EGFR [8]. Further characterization of the mechanisms of EGFR–TKI resistance is important to provide a basis for the development of effective therapies for patients who develop such resistance
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