Takeshi Hirose1, Masachika Ikegami2, Makoto Endo3, Yoshihiro Matsumoto3, Yasuharu Nakashima3, Hiroyuki Mano2, Shinji Kohsaka4. 1. Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan; Department of Orthopaedic Surgery, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 2. Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 3. Department of Orthopaedic Surgery, Graduate School of Medicine, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan. 4. Division of Cellular Signaling, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. Electronic address: skohsaka@ncc.go.jp.
Abstract
OBJECTIVES: Exon 20 insertion mutations of epidermal growth factor receptor (EGFR) have been identified as oncogenic mutations in general; however, the functional relevance of each remains largely uninvestigated. Herein, we comprehensively assessed the functional significance of insertion mutations of EGFR exon 20. MATERIALS AND METHODS: The transforming potential and drug sensitivities of 25 EGFR recurrent mutants, including twenty-one exon 20 insertions, were evaluated using the mixed-all-nominated-in-one method. RESULTS: The sensitivity of EGFR exon 20 insertions to EGFR tyrosine kinase inhibitors (TKIs) was generally lower than that of the L858R mutation or exon 19 deletions. The results were also confirmed through an in vivo drug test. All of the exon 20 insertions were resistant to gefitinib and afatinib, whereas several mutants were sensitive to osimertinib. EGFR exon 20 insertions exhibited relatively good responses to poziotinib and mobocertinib. CONCLUSIONS: EGFR exon 20 insertions were shown to have different degrees of sensitivity to EGFR TKIs. This extensive assessment of EGFR exon 20 insertions may provide a fundamental database for aiding in a customized mode of therapy for cancers having insertional mutations within exon 20 of EGFR, although the clinical impact of preclinical data should be validated by clinical evidence in the future.
OBJECTIVES: Exon 20 insertion mutations of epidermal growth factor receptor (EGFR) have been identified as oncogenic mutations in general; however, the functional relevance of each remains largely uninvestigated. Herein, we comprehensively assessed the functional significance of insertion mutations of EGFR exon 20. MATERIALS AND METHODS: The transforming potential and drug sensitivities of 25 EGFR recurrent mutants, including twenty-one exon 20 insertions, were evaluated using the mixed-all-nominated-in-one method. RESULTS: The sensitivity of EGFR exon 20 insertions to EGFR tyrosine kinase inhibitors (TKIs) was generally lower than that of the L858R mutation or exon 19 deletions. The results were also confirmed through an in vivo drug test. All of the exon 20 insertions were resistant to gefitinib and afatinib, whereas several mutants were sensitive to osimertinib. EGFR exon 20 insertions exhibited relatively good responses to poziotinib and mobocertinib. CONCLUSIONS: EGFR exon 20 insertions were shown to have different degrees of sensitivity to EGFR TKIs. This extensive assessment of EGFR exon 20 insertions may provide a fundamental database for aiding in a customized mode of therapy for cancers having insertional mutations within exon 20 of EGFR, although the clinical impact of preclinical data should be validated by clinical evidence in the future.
Authors: James Chih-Hsin Yang; Martin Schuler; Sanjay Popat; Satoru Miura; Keunchil Park; Antonio Passaro; Filippo De Marinis; Flavio Solca; Angela Märten; Edward S Kim Journal: Front Oncol Date: 2022-04-28 Impact factor: 5.738
Authors: Mohd Imran; Shah Alam Khan; Mohammed Kanan Alshammari; Meshal Ayedh Alreshidi; Abeer Abdullah Alreshidi; Rawan Sulaiman Alghonaim; Fayez Aboud Alanazi; Sultan Alshehri; Mohammed M Ghoneim; Faiyaz Shakeel Journal: Biomedicines Date: 2021-12-17