Related Experiment Videos
Targeting non-small cell lung cancer with small-molecule EGFR tyrosine kinase inhibitors
Mahaveer Singh1, Hemant R Jadhav2
1School of Pharmaceutical Sciences, Jaipur National University, 302017 Rajasthan, India.
Abstract:
Epidermal growth factor (EGFR) tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, show excellent clinical efficacy for patients with non-small cell lung cancer (NSCLC) with EGFR mutations, including Exon 19 deletion and single-point substitution, and L858R of exon 21. The reason for the reduction in effectiveness of these EGFR TKIs is the T790M gatekeeper mutation in the ATP-binding pocket of Exon 20, which increases the affinity of EGFR for ATP. Newer EGFR TKIs, such as afatinib, osimertinib, rociletinib, EGF816 and ASP8273, selectively target T790M mutants, sparing wild-type EGFR. EGFR TKIs have fewer adverse effects than chemotherapy and also improve progression-free survival. Combination therapy of EGFR TKIs with anti-EGFR antibodies is recommended for overcoming the problem of resistance to some extent. This review could help medicinal chemists to design novel EGFR TKIs against NSCLC.
Insights
First-generation EGFR TKIs are effective for non-small cell lung cancer (NSCLC) with EGFR mutations but face resistance from the T790M mutation. Newer TKIs target this resistance, offering improved outcomes for NSCLC patients.
Area of Science:
- Oncology
- Pharmacology
- Molecular Biology
Background:
- Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) like gefitinib and erlotinib demonstrate significant efficacy in non-small cell lung cancer (NSCLC) patients harboring specific EGFR mutations (Exon 19 deletion, L858R).
- Resistance to these first-generation EGFR TKIs often arises due to the T790M gatekeeper mutation in Exon 20, which enhances EGFR's affinity for ATP.
Purpose of the Study:
- To review the efficacy of current and emerging EGFR TKIs in NSCLC treatment.
- To discuss the mechanisms of resistance to EGFR TKIs, particularly the T790M mutation.
- To explore strategies for overcoming TKI resistance, including novel drug design and combination therapies.
Main Methods:
- Literature review of clinical studies and research articles on EGFR TKIs in NSCLC.
- Analysis of molecular mechanisms underlying EGFR mutations and TKI resistance.
- Evaluation of the therapeutic potential of newer generation EGFR TKIs and combination strategies.
Main Results:
- First-generation EGFR TKIs show clinical efficacy but are limited by the T790M resistance mutation.
- Next-generation EGFR TKIs (afatinib, osimertinib, rociletinib, etc.) are designed to selectively target T790M mutants while sparing wild-type EGFR.
- EGFR TKIs generally exhibit fewer adverse effects compared to chemotherapy and improve progression-free survival.
- Combination therapy with anti-EGFR antibodies shows promise in overcoming resistance.
Conclusions:
- Novel EGFR TKIs offer a promising therapeutic avenue for NSCLC patients, particularly those with T790M resistance mutations.
- Combination therapies may enhance treatment efficacy and overcome resistance mechanisms.
- This review provides insights for medicinal chemists in designing next-generation EGFR TKIs for improved NSCLC management.