Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells.
Bottom Line: However, most patients ultimately relapse due to the development of drug resistance.In this study, we have discovered a STAT3-dependent Akt activation that impairs the efficacy of gefitinib.Such a de-repression of STAT3 in turn fostered Akt activation.
Hyperactivation of Epidermal Growth Factor Receptor (EGFR) tyrosine kinase is prevalent in human lung cancer and its inhibition by the tyrosine kinase inhibitors (TKIs), including gefitinib and erlotinib, initially controls tumor growth. However, most patients ultimately relapse due to the development of drug resistance. In this study, we have discovered a STAT3-dependent Akt activation that impairs the efficacy of gefitinib. Mechanistically, gefitinib increased association of EGFR with STAT3, which de-repressed STAT3 from SOCS3, an upstream suppressor of STAT3. Such a de-repression of STAT3 in turn fostered Akt activation. Genetic or pharmacological inhibition of STAT3 abrogated Akt activation and combined gefitinib with STAT3 inhibition synergistically reduced the growth of the tumor cells. Taken together, this study suggests that activation of STAT3 is an intrinsic mechanism of drug resistance in response to EGFR TKIs. Combinational targeting on both EGFR and STAT3 may enhance the efficacy of gefitinib or other EGFR TKIs in lung cancer.
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Mentions: STAT family proteins, STAT3 in particular, play an essential role in EGFR-mediated cellular responses . Emerging evidence has demonstrated that hyperactivation of STAT3 contributes to carcinogenesis in a variety of cancer types and disruption of the STAT3 signaling decreased tumor growth [23, 24]. Inhibition of EGFR by gefitinib is supposed to be able to down regulate the subsequent STAT3 activity. However, time course test showed that gefitinib treatment, in fact, induces STAT3 activation in A549 cells (Fig. 3). After exposure to gefitinib at both 4μM and 8μM, a rapid increase of phosphorylation of STAT3 in tyrosine 705 residue (Y705) was observed and the intensity of which is not affected by different doses of gefitinib. Interestingly, the trend of gefitinib-induced STAT3 activation is accordant with the recovery pattern of Akt after gefitinib treatment, indicating potential interaction between these two pathways (Fig.3)