Background
Acquired resistance after EGFR-tyrosine kinase inhibitor (TKI) treatment is the rule rather than the exception. Overcoming resistance to EGFR-TKIs is essential if we are to develop better therapeutic strategies for lung cancer patients. Here, we examine the effector signaling pathways underlying TKI resistance and propose targets to overcome the resistance of lung adenocarcinoma (LAC) to TKI.
Conclusion
Treatment with an EGFR-TKI plus cosuppression of NF-κB and AICDA may be a promising strategy to overcome EGFR-TKI resistance in LACs.
Methods
We compared the expression of NF-κB, AICDA, Akt, IL-6, Jak2, and Stat3 by EGFR-TKI-resistant and EGFR-TKI-sensitive LAC cell lines, and by LAC patients treated with EGFR-TKIs; we then evaluated links between expression and treatment responses. We also examined the therapeutic effects of NF-κB and AICDA inhibition in EGFR-TKI-resistant LACs.
Results
NF-κB and AICDA were more expressed by EGFR-TKI-resistant LACs than by EGFR-TKI-sensitive LACs. EGFR-TKIs induced a dose-dependent increase in the expression of NF-κB, AICDA, and IL-6. Inhibition of NF-κB suppressed the expression of AICDA, Akt, and IL-6 in EGFR-TKI-resistant and EGFR-TKI-sensitive LACs, whereas knockdown of AICDA suppressed the expression of NF-κB and Akt in both cell types. Treating EGFR-TKI-resistant LACs with an EGFR-TKI, alongside cosuppression of NF-κB and AICDA, had a significant therapeutic effect.