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Updated: Jan 19, 2026
Induced Electric Fields
Applied electric fields suppress osimertinib-induced cytotoxicity via inhibiting FOXO3a nuclear translocation through
Li Li1, Chen Hu1, Conghua Lu1
1Department of Respiratory Disease, Daping Hospital, Army Medical University, Chongqing, China.
Abstract:
Osimertinib is a third-generation epidermal growth factor receptor tyrosine kinase inhibitor against T790M-mutant non-small cell lung cancer (NSCLC). Acquired resistance to osimertinib is a growing clinical challenge that is not fully understood. Endogenous electric fields (EFs), components of the tumor microenvironment, are associated with cancer cell migration and proliferation. However, the impact of EFs on drug efficiency has not been studied. In this study, we observed that EFs counteracted the effects of osimertinib. EFs of 100 mV/mm suppressed osimertinib-induced cell death and promoted cell proliferation. Transcriptional analysis revealed that the expression pattern induced by osimertinib was altered by EFs stimulation. KEGG analysis showed that differential expression genes were mostly enriched in PI3K-AKT pathway. Then, we found that osimertinib inhibited AKT phosphorylation, while EFs stimulation resulted in significant activation of AKT, which could override the effects generated by osimertinib. Importantly, pharmacological inhibition of PI3K/AKT by LY294002 diminished EF-induced activation of AKT and restored the cytotoxicity of osimertinib suppressed by EFs, which proved that AKT activation was essential for EFs to attenuate the efficacy of osimertinib. Furthermore, activation of AKT by EFs led to phosphorylation of forkhead box O3a (FOXO3a), and reduction in nuclear translocation of FOXO3a induced by osimertinib, resulting in decreased expression of Bim and attenuated cytotoxicity of osimertinib. Taken together, we demonstrated that EFs suppressed the antitumor activity of osimertinib through AKT/FOXO3a/Bim pathway, and combination of PI3K/AKT inhibitor with osimertinib counteracted the effects of EFs. Our findings provided preliminary data for therapeutic strategies to enhance osimertinib efficacy in NSCLC patients.
Insights
Endogenous electric fields (EFs) reduce osimertinib effectiveness in non-small cell lung cancer (NSCLC) by activating the AKT pathway. Combining AKT inhibitors with osimertinib may overcome this resistance, improving NSCLC treatment.
Area of Science:
- Oncology
- Cancer Biology
- Molecular Therapeutics
Background:
- Acquired resistance to osimertinib presents a significant clinical challenge in treating T790M-mutant non-small cell lung cancer (NSCLC).
- Endogenous electric fields (EFs) are emerging as a critical component of the tumor microenvironment, influencing cancer cell behavior.
- The specific impact of EFs on the efficacy of targeted therapies like osimertinib remains largely unexplored.
Purpose of the Study:
- To investigate the effect of endogenous electric fields (EFs) on the efficacy of osimertinib in non-small cell lung cancer (NSCLC).
- To elucidate the molecular mechanisms by which EFs modulate osimertinib's anti-cancer activity.
- To explore potential therapeutic strategies combining EFs modulation with osimertinib treatment.
Main Methods:
- Cell culture models of NSCLC treated with osimertinib and varying electric field strengths.
- Transcriptional analysis (RNA sequencing) and KEGG pathway enrichment analysis.
- Western blotting to assess protein phosphorylation, including AKT and FOXO3a.
- Pharmacological inhibition of the PI3K/AKT pathway using LY294002.
Main Results:
- Electric fields (100 mV/mm) suppressed osimertinib-induced apoptosis and promoted NSCLC cell proliferation.
- EFs altered the osimertinib-induced gene expression profile, with significant enrichment in the PI3K-AKT pathway.
- EFs induced AKT activation, overriding osimertinib's inhibitory effect on AKT phosphorylation.
- Inhibition of AKT restored osimertinib's cytotoxicity, confirming AKT activation's role in EF-mediated resistance.
- EF-induced AKT activation led to FOXO3a phosphorylation and reduced its nuclear translocation, decreasing Bim expression and diminishing osimertinib's efficacy.
Conclusions:
- Endogenous electric fields suppress the antitumor activity of osimertinib in NSCLC by activating the AKT/FOXO3a/Bim pathway.
- Combining PI3K/AKT inhibitors with osimertinib can counteract the resistance induced by EFs.
- These findings offer preliminary insights for developing therapeutic strategies to enhance osimertinib efficacy in NSCLC patients facing EF-mediated resistance.
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