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Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib
Published on: June 26, 2019
Clinical and comparative utility of afatinib in non-small cell lung cancer
Manolo D'Arcangelo1, Fred R Hirsch1
1University of Colorado Denver, Department of Medical Oncology, Aurora, CO, USA.
Abstract:
The first targeted agents approved for non-small cell lung cancer (NSCLC) treatment, the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, have an impressive activity in the presence of activating mutations of the EGFR gene. However, all patients develop acquired resistance principally through secondary mutations (T790M), HER2 amplification, MET amplification, and other molecular aberrations. An attempt to overcome EGFR TKI resistance has been through the development of irreversible blockers. Afatinib is an irreversible inhibitor of the tyrosine kinase activity of all members of the HER family. The pharmacologic properties of afatinib (formation of covalent bonds, inhibition of other family members, and in vitro and in vivo activity on T790M mutation positive tumors) made this drug particularly appealing to study in clinic. Therefore, an intense program of clinical research (LUX-Lung program) was started and clinical results have shown very encouraging activity profiles in patients harboring EGFR activating mutations and in those with acquired resistance to reversible TKIs.
Insights
Afatinib, an irreversible EGFR inhibitor, shows promise against non-small cell lung cancer (NSCLC) with EGFR mutations. It demonstrates activity in patients resistant to earlier EGFR tyrosine kinase inhibitors (TKIs).
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib are effective for non-small cell lung cancer (NSCLC) with EGFR mutations.
- Acquired resistance to EGFR TKIs often develops due to secondary mutations (e.g., T790M), HER2 amplification, or MET amplification.
- Irreversible inhibitors are being developed to overcome resistance mechanisms in NSCLC treatment.
Purpose of the Study:
- To evaluate the efficacy of afatinib, an irreversible pan-HER inhibitor, in NSCLC patients.
- To assess afatinib's activity in patients with EGFR activating mutations and acquired resistance to reversible TKIs.
- To explore the clinical utility of afatinib in overcoming EGFR TKI resistance.
Main Methods:
- Afatinib was studied as an irreversible inhibitor targeting all members of the HER family.
- Pharmacologic properties, including covalent bond formation and activity against T790M mutations, were investigated.
- Clinical research, including the LUX-Lung program, was conducted to assess afatinib's efficacy.
Main Results:
- Afatinib demonstrated significant in vitro and in vivo activity against T790M mutation-positive tumors.
- Clinical results from the LUX-Lung program showed encouraging activity profiles.
- Afatinib exhibited efficacy in patients with EGFR activating mutations and acquired resistance to reversible TKIs.
Conclusions:
- Afatinib is a promising irreversible inhibitor for NSCLC treatment, particularly in patients with EGFR mutations.
- Its ability to overcome acquired resistance mechanisms makes it a valuable therapeutic option.
- Afatinib represents a significant advancement in targeting resistant NSCLC.
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