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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
Molecular predictors of response to epidermal growth factor receptor antagonists in non-small-cell lung cancer
Lecia V Sequist1, Daphne W Bell, Thomas J Lynch
1Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA, USA.
Abstract:
In the last 5 years the epidermal growth factor receptor (EGFR) has emerged as one of the most important targets for drug development in oncology. Monoclonal antibodies targeting the external domain of EGFR have been shown to have clinical benefit in colorectal and head and neck cancer when combined with chemotherapy and/or radiation. Small molecules that inhibit the tyrosine kinase (TK) domain of EGFR have become critical new weapons in the treatment of non-small-cell lung cancer (NSCLC). The discovery that mutations in the TK domain are associated with dramatic and sustained responses to EGFR TK inhibitors (TKIs) has allowed the design of trials to test these agents as potential first-line therapies and has provided a fascinating window into the future of genotype-directed targeted therapy. Recent advances in understanding the biologic basis of acquired resistance to these agents have great potential to improve the clinical effectiveness of this class of drugs. This review summarizes the biology of EGFR in NSCLC, the clinical and molecular predictors of benefit from treatment with EGFR TKIs, the use of patient-specific molecular profiling, and future directions of clinical and basic scientific research.
Insights
Epidermal growth factor receptor (EGFR) inhibitors are revolutionizing cancer treatment, particularly in non-small-cell lung cancer (NSCLC). Understanding EGFR mutations and resistance mechanisms is key to developing more effective, genotype-directed therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) is a key target in oncology drug development.
- EGFR-targeting monoclonal antibodies and small molecule tyrosine kinase inhibitors (TKIs) show clinical benefit in various cancers.
- EGFR TKIs are crucial in treating non-small-cell lung cancer (NSCLC).
Purpose of the Study:
- To review the biology of EGFR in NSCLC.
- To discuss clinical and molecular predictors of response to EGFR TKIs.
- To explore future directions in EGFR-targeted therapy research.
Main Methods:
- Literature review of EGFR biology and targeted therapies in NSCLC.
- Analysis of clinical trial data and molecular profiling studies.
- Synthesis of recent advances in understanding EGFR TKI resistance.
Main Results:
- EGFR mutations in the tyrosine kinase (TK) domain predict response to TKIs in NSCLC.
- Genotype-directed therapy is a growing paradigm in cancer treatment.
- Understanding acquired resistance mechanisms is vital for improving TKI efficacy.
Conclusions:
- EGFR TKIs represent a significant advancement in NSCLC treatment.
- Personalized medicine approaches, guided by molecular profiling, are essential.
- Further research into resistance mechanisms will enhance the clinical utility of EGFR inhibitors.
