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In vitro modeling to determine mutation specificity of EGFR tyrosine kinase inhibitors against clinically relevant EGFR mutants in non-small-cell lung cancer

2015; Impact Journals LLC; Volume: 6; Issue: 36 Linguagem: Inglês

10.18632/oncotarget.5887

1949-2553

Toshiyuki Hirano, Hiroyuki Yasuda, Tetsuo Tani, Junko Hamamoto, Ayano Oashi, Kota Ishioka, Daisuke Arai, Shigenari Nukaga, Masayoshi Miyawaki, Ichiro Kawada, Katsuhiko Naoki, Daniel B. Costa, Susumu Kobayashi, Tomoko Betsuyaku, Kenzo Soejima,

PI3K/AKT/mTOR signaling in cancer

// Toshiyuki Hirano 1, * , Hiroyuki Yasuda 1 , Tetsuo Tani 1, * , Junko Hamamoto 1 , Ayano Oashi 1 , Kota Ishioka 1 , Daisuke Arai 1 , Shigenari Nukaga 1 , Masayoshi Miyawaki 1 , Ichiro Kawada 1 , Katsuhiko Naoki 2 , Daniel B. Costa 3 , Susumu S. Kobayashi 3 , Tomoko Betsuyaku 1 , Kenzo Soejima 1 1 Division of Pulmonary Medicine, Department of Medicine, Keio University, School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 2 Keio Cancer Center, Keio University, School of Medicine 35 Shinanomachi, Shinjuku-ku, Tokyo, Japan 3 Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA * These authors have contributed equally to this work Correspondence to: Hiroyuki Yasuda, e-mail: hiroyukiyasuda@a8.keio.jp Kenzo Soejima, e-mail: ksoejima@cpnet.med.keio.ac.jp Keywords: EGFR mutation, EGFR tyrosine kinase inhibitors, EGFR exon 20 insertion mutations, in vitro modeling, lung cancer Received: August 18, 2015 Accepted: October 03, 2015 Published: October 15, 2015 ABSTRACT EGFR mutated lung cancer accounts for a significant subgroup of non-small-cell lung cancer (NSCLC). Over the last decade, multiple EGFR tyrosine kinase inhibitors (EGFR-TKIs) have been developed to target mutated EGFR. However, there is little information regarding mutation specific potency of EGFR-TKIs against various types of EGFR mutations. The purpose of this study is to establish an in vitro model to determine the “therapeutic window” of EGFR-TKIs against various types of EGFR mutations, including EGFR exon 20 insertion mutations. The potency of 1 st (erlotinib), 2 nd (afatinib) and 3 rd (osimertinib and rociletinib) generation EGFR-TKIs was compared in vitro for human lung cancer cell lines and Ba/F3 cells, which exogenously express mutated or wild type EGFR . An in vitro model of mutation specificity was created by calculating the ratio of IC50 values between mutated and wild type EGFR. The in vitro model identified a wide therapeutic window of afatinib for exon 19 deletions and L858R and of osimertinib and rociletinib for T790M positive mutations. The results obtained with our models matched well with previously reported preclinical and clinical data. Interestingly, for EGFR exon 20 insertion mutations, most of which are known to be resistant to 1 st and 2 nd generation EGFR-TKIS, osimertinib was potent and presented a wide therapeutic window. To our knowledge, this is the first report that has identified the therapeutic window of osimertinib for EGFR exon 20 insertion mutations. In conclusion, this model will provide a preclinical rationale for proper selection of EGFR-TKIs against clinically-relevant EGFR mutations.