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Published on: June 26, 2019
Selective antitumor activity of ibrutinib in EGFR-mutant non-small cell lung cancer cells
Wen Gao1, Michael Wang1, Li Wang1
1Department of Thoracic and Cardiovascular Surgery (WG, LW, HL, SW, BD, JAR, WLH, SGS, BF) and Department of Lymphoma and Myeloma (MW, ZO, LZ) and Department of Thoracic/Head and Neck Medical Oncology (JVH, KAD), The University of Texas MD Anderson Cancer Center, Houston, TX; Hamon Center for Therapeutic Oncology, The Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX (JM); Department of Oncology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China (WG).
Abstract:
Ibrutinib, which irreversibly inhibits Bruton tyrosine kinase, was evaluated for antitumor activity in a panel of non-small cell lung cancer (NSCLC) cell lines and found to selectively inhibit growth of NSCLC cells carrying mutations in the epidermal growth factor receptor (EGFR) gene, including T790M mutant and erlotinib-resistant H1975 cells. Ibrutinib induced dose-dependent inhibition of phosphor-EGFR at both Y1068 and Y1173 sites, suggesting ibrutinib functions as an EGFR inhibitor. Survival was analyzed by Kaplan-Meier estimation and log-rank test. All statistical tests were two-sided. In vivo study showed that ibrutinib statistically significantly suppressed H1975 tumor growth and prolonged survival of the tumor bearing mice (n = 5 per group). The mean survival times for solvent- and erlotinib-treated mice were both 17.8 days (95% confidence interval [CI] = 14.3 to 21.3 days), while the mean survival time for ibrutinib-treated mice was 29.8 days (95% CI = 26.0 to 33.6 days, P = .008). Our results indicate that ibrutinib could be a candidate drug for treatment of EGFR-mutant NSCLC, including erlotinib-resistant tumors.
Insights
Ibrutinib selectively inhibits non-small cell lung cancer (NSCLC) growth, particularly EGFR-mutant and erlotinib-resistant types. In vivo studies show ibrutinib significantly suppresses tumor growth and prolongs survival in mice.
Area of Science:
- Oncology
- Pharmacology
Background:
- Non-small cell lung cancer (NSCLC) remains a leading cause of cancer-related mortality.
- Epidermal growth factor receptor (EGFR) mutations are key drivers in a subset of NSCLC, often leading to resistance against targeted therapies like erlotinib.
- Bruton tyrosine kinase (BTK) inhibitors are primarily known for their role in hematological malignancies.
Purpose of the Study:
- To evaluate the antitumor activity of ibrutinib, a BTK inhibitor, in NSCLC cell lines.
- To investigate ibrutinib's efficacy against EGFR-mutant and erlotinib-resistant NSCLC models.
- To determine if ibrutinib exhibits inhibitory effects on EGFR signaling.
Main Methods:
- Antitumor activity was assessed in a panel of NSCLC cell lines with varying EGFR mutation statuses.
- In vitro studies measured the inhibition of phosphorylated EGFR (p-EGFR) at specific tyrosine residues (Y1068 and Y1173).
- In vivo efficacy was evaluated in a mouse xenograft model using H1975 NSCLC cells (EGFR T790M mutant, erlotinib-resistant), with survival analysis using Kaplan-Meier estimation.
Main Results:
- Ibrutinib demonstrated selective inhibition of NSCLC cell growth, particularly in lines harboring EGFR mutations, including the T790M and erlotinib-resistant H1975 cell lines.
- Ibrutinib induced a dose-dependent decrease in p-EGFR levels at Y1068 and Y1173, indicating EGFR pathway inhibition.
- In vivo, ibrutinib significantly suppressed H1975 tumor growth and markedly prolonged survival in tumor-bearing mice compared to solvent and erlotinib controls (29.8 days vs. 17.8 days, P = .008).
Conclusions:
- Ibrutinib exhibits potent antitumor activity against EGFR-mutant NSCLC, including erlotinib-resistant phenotypes.
- The findings suggest that ibrutinib functions as an EGFR inhibitor in this context, offering a potential therapeutic strategy.
- Ibrutinib represents a promising candidate drug for treating patients with EGFR-mutant NSCLC, particularly those with acquired resistance to existing therapies.
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