The emergence of resistance to
EGF receptor (EGFR) inhibitor
therapy is a major clinical problem for patients with
non-small cell lung cancer (NSCLC). The mechanisms underlying
tumor resistance to inhibitors of the
kinase activity of EGFR are not fully understood. Here, we found that inhibition of EGFR by
erlotinib induces STAT3 phosphorylation at Tyr705 in association with increased Bcl2/Bcl-XL at both
mRNA and
protein levels in various human
lung cancer cells. PTPMeg2 is a physiologic STAT3
phosphatase that can directly dephosphorylate STAT3 at the Tyr705 site. Intriguingly, treatment of cells with
erlotinib results in downregulation of PTPMeg2 without activation of STAT3
kinases [i.e., Janus-activated
kinase (JAK2) or c-Src], suggesting that
erlotinib-enhanced phosphorylation of STAT3 may occur, at least in part, from suppression of PTPMeg2 expression. Because elevated levels of phosphorylated STAT3 (pSTAT3), Bcl2, and Bcl-XL were observed in
erlotinib-resistant
lung cancer (HCC827/ER) cells as compared with
erlotinib-sensitive parental HCC827 cells, we postulate that the
erlotinib-activated STAT3/Bcl2/Bcl-XL survival pathway may contribute to acquired resistance to
erlotinib. Both blockage of Tyr705 phosphorylation of STAT3 by
niclosamide and depletion of STAT3 by RNA interference in HCC827/ER cells reverse
erlotinib resistance.
Niclosamide in combination with
erlotinib potently represses
erlotinib-resistant
lung cancer xenografts in association with increased apoptosis in
tumor tissues, suggesting that
niclosamide can restore sensitivity to
erlotinib. These findings uncover a novel mechanism of
erlotinib resistance and provide a novel approach to overcome resistance by blocking the STAT3/Bcl2/Bcl-XL survival signaling pathway in human
lung cancer.