Abstract
Background: The major limitation of EGFR TKIs in EGFR-mutant lung cancer therapy is the development of acquired resistance. The underlying mechanisms remain unknown in about 30% of cases. NF-κB activation was encountered in the acquired resistance to EGFR TKIs. Unfortunately, none of NF-κB inhibitors has been clinically approved. The most commonly used antidiabetic drug metformin has demonstrated antitumor effects associated with NF-κB inhibition. Therefore, in this study, metformin was examined for its antitumor and antiresistance effects and underlying mechanisms.Methods: In vitro and in vivo EGFR-mutant lung cancer models with acquired resistance to EGFR TKIs were used.Results: We found that NF-κB was activated in EGFR-mutant lung cancer cells with acquired resistance to EGFR TKIs. Metformin inhibited proliferation and promoted apoptosis of lung cancer cells, especially those with acquired EGFR TKI resistance. Moreover, metformin reversed and delayed acquired resistance to EGFR TKIs as well as suppressed cancer stemness in EGFR-mutant lung cancer. Mechanistically, those effects of metformin were associated with activation of AMPK, resulting in the inhibition of downstream ERK/NF-κB signaling.Conclusions: Our data provided novel and further molecular rationale and preclinical data to support combination of metformin with EGFR TKIs to treat EGFR-mutant lung cancer patients, especially those with acquired resistance.
Highlights
The major limitation of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer therapy is the development of acquired resistance
We and others have previously reported that nuclear factor-κB (NF-κB) was activated in EGFR-mutant lung cancer with acquired resistance to EGFR TKIs [12,13,14]
In vitro cell model of acquired resistance to EGFR TKIs was established by culturing sensitive EGFR-mutant lung cancer HCC827 or PC9 cells in gefitinib or osimertinib with elevating concentration as we previously reported [12]
Summary
The major limitation of EGFR TKIs in EGFR-mutant lung cancer therapy is the development of acquired resistance. The underlying mechanisms remain unknown in about 30% of cases. NF-κB activation was encountered in the acquired resistance to EGFR TKIs. none of NF-κB inhibitors has been clinically approved. In this study, metformin was examined for its antitumor and antiresistance effects and underlying mechanisms. EGFR tyrosine kinase inhibitors (TKIs) have demonstrated dramatic efficacy in non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations [1]. Since the clinical efficacy of TKIs is limited by the development of acquired resistance, further investigation of novel molecular mechanisms is essential to develop strategies to overcome or delay the acquired resistance to TKIs in EGFR-mutant lung cancer
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