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The Establishment of a Lung Colonization Assay for Circulating Tumor Cell Visualization in Lung Tissues
Published on: June 16, 2018
Met in lung cancer
1Department of Biochemistry; Massey Cancer Center; Virginia Commonwealth University; Richmond, VA USA.
Abstract:
Receptor tyrosine kinases play important roles in the biology of many tumor cell types. In approximately 10% of non-small cell lung cancer (NSCLC) patients mutational activation of the epidermal growth factor receptor (EGFR) results in tumor cells that are exquisitely addicted to signaling by this receptor. (1) Thus expression of mutant active EGFR but in general not wild-type EGFR predisposes NSCLC cells to inhibitors of EGFR/ErbB2. Use of EGFR inhibitory agents such as gefitinib for this subset of NSCLC patients causes tumor regression and disease stabilization for 12-18 mo, after which tumor cells become resistant to the drug. (2) Initial studies identified a second mutation within the EGFR, which results in the resistance of the tyrosine kinase to gefitinib, as a major cause of reduced tumor control. (3) This has resulted in the development of newer EGFR inhibitors, e.g., afatinib, which inhibited double mutant EGFR. (4) In a subset of these patients, however, resistance to gefitinib was not associated with EGFR mutations. (5) Clearly, other mechanisms of gefitinib resistance must be at play.
Insights
Targeted therapy for non-small cell lung cancer (NSCLC) using epidermal growth factor receptor (EGFR) inhibitors like gefitinib shows initial success. However, acquired resistance, sometimes independent of EGFR mutations, necessitates exploring alternative resistance mechanisms.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Receptor tyrosine kinases are crucial in cancer cell biology.
- Activating mutations in epidermal growth factor receptor (EGFR) drive 10% of non-small cell lung cancer (NSCLC) cases.
- EGFR-addicted NSCLC cells respond to EGFR inhibitors like gefitinib.
Purpose of the Study:
- To investigate mechanisms of acquired resistance to EGFR inhibitors in NSCLC.
- To understand why some NSCLC patients develop resistance to gefitinib independent of EGFR mutations.
Main Methods:
- Analysis of EGFR mutations in NSCLC patients.
- Clinical observation of tumor response and resistance to gefitinib and afatinib.
- Identification of resistance mechanisms beyond secondary EGFR mutations.
Main Results:
- Gefitinib treatment leads to initial tumor regression in EGFR-mutated NSCLC.
- Acquired resistance develops in 12-18 months, often due to a second EGFR mutation.
- A subset of patients develops gefitinib resistance without secondary EGFR mutations.
Conclusions:
- While secondary EGFR mutations explain some gefitinib resistance, other mechanisms are involved.
- Further research is needed to elucidate non-EGFR-mediated resistance pathways.
- Understanding diverse resistance mechanisms is critical for improving NSCLC treatment strategies.
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