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Updated: Nov 20, 2025
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
Moving beyond epidermal growth factor receptor resistance in metastatic non-small cell lung cancer - a drug
Julia Lai-Kwon1, Crescens Tiu1, Abhijit Pal1
1Drug Development Unit, Royal Marsden Hospital and Institute of Cancer Research, Sutton, United Kingdom.
Abstract:
Epidermal Growth Factor Receptor (EGFR) mutations are the most common targetable oncogenic driver mutation in metastatic non-small lung cancer (NSCLC). There have been significant advances in the management of metastatic EGFR-mutant NSCLC from the advent of first and second generation EGFR inhibitors to, more recently, the third-generation inhibitor osimertinib. Osimeritinib is now established as first-line therapy on the basis of improved outcomes compared to first and second generation agents. However, despite excellent initial response rates, responses may not be durable due to the development of acquired resistance. Understanding these mechanisms of resistance is critical to the development of rational drug and drug combinations capable of circumventing them. We discuss the major mechanisms of resistance to first, second and third generation EGFR TKIs. The potential of drug combinations utilising chemotherapy, immunotherapy and anti-angiogenic drugs are explored. We examine strategies to aid drug development, including circulating tumour DNA and novel trial designs.
Insights
Acquired resistance limits the durability of osimertinib therapy in metastatic non-small cell lung cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) mutations. Understanding resistance mechanisms is key to developing novel drug combinations for improved patient outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal Growth Factor Receptor (EGFR) mutations drive metastatic non-small cell lung cancer (NSCLC).
- First, second, and third-generation EGFR tyrosine kinase inhibitors (TKIs), including osimertinib, have advanced NSCLC treatment.
- Osimertinib is a preferred first-line therapy, but acquired resistance limits long-term efficacy.
Purpose of the Study:
- To review major mechanisms of acquired resistance to EGFR TKIs in NSCLC.
- To explore potential drug combinations to overcome resistance.
- To examine strategies for accelerating drug development in this field.
Main Methods:
- Literature review of resistance mechanisms to first, second, and third-generation EGFR TKIs.
- Exploration of combination therapies including chemotherapy, immunotherapy, and anti-angiogenic drugs.
- Discussion of novel drug development strategies such as circulating tumor DNA (ctDNA) analysis and innovative clinical trial designs.
Main Results:
- Acquired resistance to EGFR TKIs is a significant clinical challenge in EGFR-mutant NSCLC.
- Various resistance mechanisms exist for first, second, and third-generation TKIs.
- Drug combinations and novel trial designs show promise for overcoming resistance.
Conclusions:
- Understanding EGFR TKI resistance mechanisms is crucial for developing effective treatment strategies.
- Combination therapies hold potential for improving durable responses in resistant NSCLC.
- Advanced strategies like ctDNA monitoring and novel trial designs are vital for future drug development.
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