Research Papers:

Gefitinib resistance resulted from STAT3-mediated Akt activation in lung cancer cells

Kai Wu, Qingshan Chang, Yongju Lu, Ping Qiu, Bailing Chen, Chitra Thakur, Jiaying Sun, Lingzhi Li, Anjaneyulu Kowluru and Fei Chen _

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Oncotarget. 2013; 4:2430-2438. https://doi.org/10.18632/oncotarget.1431

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Kai Wu1, Qingshan Chang1, Yongju Lu1, Ping Qiu1, Bailing Chen1, Chitra Thakur1, Jiaying Sun1, Lingzhi Li1, Anjaneyulu Kowluru1, Fei Chen1

1 Department of Pharmaceutical Sciences, Eugene Applebaum College of Pharmacy and Health Sciences, Wayne State University, Detroit, MI, USA


Fei Chen, email:

Keywords: Gefitinib, EGFR, STAT3, Akt recovery

Received: September 22, 2013 Accepted: November 22, 2013 Published: November 24, 2013


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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