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Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017
Fulvestrant increases gefitinib sensitivity in non-small cell lung cancer cells by upregulating let-7c expression
Hua Shen1, Jinyuan Liu2, Rong Wang1
1Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
Abstract:
Patients with non-small cell lung cancer (NSCLC) who have activating epidermal growth factor receptor (EGFR) mutations benefit from treatment with EGFR-tyrosine kinase inhibitors (EGFR-TKIs), namely, gefitinib and erlotinib. However, these patients eventually develop resistance to EGFR-TKIs. About 50% of this acquired resistance may be the result of a secondary mutation in the EGFR gene, such as the one corresponding to T790M. In our previous study, we found that combined treatment with fulvestrant and gefitinib decreases the proliferation of H1975 NSCLC cells, compared to treatment with either fulvestrant or gefitinib alone; however, the molecular mechanism for the improved effects of the combination treatment are still unknown. In this study, we confirmed that fulvestrant increases the gefitinib sensitivity of H1975 cells and found that let-7c was most upregulated in the fulvestrant-treated cells. Our data revealed that let-7c increases gefitinib sensitivity by repressing RAS and inactivating the phosphoinositide 3-kinase (PI3K)/AKT and mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways. Taken together, our findings suggest that let-7c plays an important role in fulvestrant-induced upregulation of gefitinib sensitivity in H1975 cells.
Insights
Fulvestrant enhances gefitinib sensitivity in non-small cell lung cancer (NSCLC) by upregulating let-7c. This microRNA inhibits proliferation by targeting RAS and inactivating PI3K/AKT and MEK/ERK pathways, overcoming EGFR-TKI resistance.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) patients with activating epidermal growth factor receptor (EGFR) mutations benefit from EGFR-tyrosine kinase inhibitors (EGFR-TKIs).
- Acquired resistance to EGFR-TKIs, often due to secondary mutations like T790M, limits long-term treatment efficacy.
- The molecular mechanisms underlying combination therapies for overcoming EGFR-TKI resistance remain incompletely understood.
Purpose of the Study:
- To investigate the molecular mechanisms by which fulvestrant enhances gefitinib sensitivity in H1975 NSCLC cells.
- To identify key molecular players involved in the synergistic effects of fulvestrant and gefitinib combination therapy.
- To elucidate how fulvestrant treatment impacts signaling pathways crucial for NSCLC cell proliferation and drug resistance.
Main Methods:
- Treatment of H1975 NSCLC cells with fulvestrant and gefitinib, individually and in combination.
- Quantitative analysis of let-7c microRNA expression levels following fulvestrant treatment.
- Assessment of the impact of let-7c on RAS, phosphoinositide 3-kinase (PI3K)/AKT, and mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways.
Main Results:
- Fulvestrant treatment significantly increased gefitinib sensitivity in H1975 NSCLC cells.
- let-7c microRNA was markedly upregulated in cells treated with fulvestrant.
- Upregulated let-7c was found to repress RAS and inactivate the PI3K/AKT and MEK/ERK signaling pathways, thereby enhancing gefitinib sensitivity.
Conclusions:
- let-7c plays a critical role in mediating fulvestrant-induced enhancement of gefitinib sensitivity in H1975 NSCLC cells.
- The let-7c/RAS/PI3K-AKT/MEK-ERK axis represents a potential therapeutic target for overcoming acquired resistance to EGFR-TKIs.
- Combination therapy with fulvestrant and gefitinib shows promise for improving treatment outcomes in NSCLC patients resistant to EGFR-TKIs.
