Kenichi Suda1, Hiroshi Mizuuchi2, Isao Murakami3, Hidetaka Uramoto4, Fumihiro Tanaka4, Katsuaki Sato2, Toshiki Takemoto2, Takuya Iwasaki2, Yoshitaka Sekido5, Yasushi Yatabe6, Tetsuya Mitsudomi2. 1. Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan. Electronic address: ascaris@surg2.med.kyushu-u.ac.jp. 2. Division of Thoracic Surgery, Department of Surgery, Kinki University Faculty of Medicine, 377-2 Ohno-higashi, Osaka-Sayama, Japan. 3. Department of Respiratory Medicine, Higashi-Hiroshima Medical Center, 513 Jike, Saijo-Cho, Higashi-Hiroshima, Japan. 4. Second Department of Surgery, School of Medicine, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu, Japan. 5. Division of Molecular Oncology, Aichi Cancer Center Research Institute, 1-1 Kanokoden, Chikusa-ku, Nagoya, Japan. 6. Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, 1-1 Kanokoden, Chikusa-ku, Nagoya, Japan.
Abstract
OBJECTIVES: 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. MATERIALS AND METHODS: 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. RESULTS AND CONCLUSION: 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.
OBJECTIVES:Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) often provide dramatic responses in lung cancerpatients with somatic EGFR mutation. However, acquired resistance to the drugs usually emerges within a few years. EGFRT790M 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 cancerpatients 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. MATERIALS AND METHODS: 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. RESULTS AND CONCLUSION: 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 clinicaltumor 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 cancerpatients with EGFR mutations.