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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS. Meshes: Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Drug Resistance, Neoplasm, ErbB Receptors, Female, Gene Amplification, Gene Dosage, Humans, Lung Neoplasms, Male, Middle Aged, Mutation, Neoplasm Staging, Nuclear Proteins, Prognosis, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-met, Risk Factors.
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Is cRKL amplification rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation? Context: Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancer patients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFR T790M secondary mutation, MET gene amplification, and transformation to small cell lung cancer are well-validated mechanisms that underlie acquisition of resistance to EGFR-TKIs. In addition, many molecular aberrations have been reported as candidates for mechanisms of acquired resistance to EGFR-TKIs. Amplification of the CRKL gene was reportedly observed in 1 of 11 lung cancer patients with EGFR mutations who acquired resistance to EGFR-TKI. This study is the first report, to our knowledge, that validated the role of CRKL gene amplification as a mechanism for acquisition of resistance to EGFR-TKIs. We analyzed CRKL gene copy numbers, using a quantitative real-time PCR method, in 2 in vitro acquired-resistance cell-line models: 11 clinical samples from patients who developed acquired resistance to EGFR-TKIs, and 39 tumor specimens obtained from 7 autopsy patients whose cancers acquired resistance to EGFR-TKIs. Mutational status of EGFR codon 790 and copy numbers for the MET gene were also determined.
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In analysis for in vitro models, CRKL gene copy numbers were identical between EGFR-TKI-sensitive parental cells and their acquired resistant descendant cells. In addition, we found no clinical tumor specimens with acquired EGFR-TKI resistance to harbor amplified CRKL genes. These results indicate that CRKL gene amplification is rare in acquisition of resistance to EGFR-TKIs in lung cancer patients with EGFR mutations. Final Decision: yes