ID 57276
Author
Makimoto, Go Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Ohashi, Kadoaki Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Tomida, Shuta Okayama University Hospital Biobank, Okayama University Hospital
Nishii, Kazuya Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Matsubara, Takehiro Okayama University Hospital Biobank, Okayama University Hospital
Kayatani, Hiroe Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Higo, Hisao Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Ninomiya, Kiichiro Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Sato, Akiko Department of Respiratory Medicine, Okayama University Hospital
Watanabe, Hiromi Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Kano, Hirohisa Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Ninomiya, Takashi Department of Respiratory Medicine, Okayama University Hospital
Kubo, Toshio Center for Clinical Oncology, Okayama University Hospital
Rai, Kammei Department of Respiratory Medicine, Okayama University Hospital
Ichihara, Eiki Department of Respiratory Medicine, Okayama University Hospital
Hotta, Katsuyuki Center of Innovative Clinical Medicine, Okayama University Hospital
Tabata, Masahiro Center for Clinical Oncology, Okayama University Hospital
Toyooka, Shinichi Okayama University Hospital Biobank, Okayama University Hospital
Takata, Minoru Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Graduate School of Biostudies, Radiation Biology Center, Kyoto University
Maeda, Yoshinobu Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
Kiura, Katsuyuki Department of Respiratory Medicine, Okayama University Hospital
Abstract
Introduction
The highly selective ALK receptor tyrosine kinase (ALK) inhibitor alectinib is standard therapy for ALK-positive lung cancers; however, some tumors quickly develop resistance. Here, we investigated the mechanism associated with rapid acquisition of resistance using clinical samples.
Methods
Autopsied samples were obtained from lung, liver, and renal tumors from a 51-year-old male patient with advanced ALK-positive lung cancer who had acquired resistance to alectinib in only 3 months. We established an alectinib-resistant cell line (ABC-14) from pleural effusion and an alectinib/crizotinib-resistant cell line (ABC-17) and patient-derived xenograft (PDX) model from liver tumors. Additionally, we performed next-generation sequencing, direct DNA sequencing, and quantitative real-time reverse transcription polymerase chain reaction.
Results
ABC-14 cells harbored no ALK mutations and were sensitive to crizotinib while also exhibiting MNNG HOS transforming gene (MET) gene amplification and amphiregulin overexpression. Additionally, combined treatment with crizotinib/erlotinib inhibited cell growth. ABC-17 and PDX tumors harbored ALK G1202R, and PDX tumors metastasized to multiple organs in vivo, whereas the third-generation ALK-inhibitor, lorlatinib, diminished tumor growth in vitro and in vivo. Next-generation sequencing indicated high tumor mutation burden and heterogeneous tumor evolution. The autopsied lung tumors harbored ALK G1202R (c. 3604 G>A) and the right renal metastasis harbored ALK G1202R (c. 3604 G>C); the mutation thus comprised different codon changes.
Conclusions
High tumor mutation burden and heterogeneous tumor evolution might be responsible for rapid acquisition of alectinib resistance. Timely lorlatinib administration or combined therapy with an ALK inhibitor and other receptor tyrosine-kinase inhibitors might constitute a potent strategy.
Keywords
ALK G1202R
Alectinib
Amphiregulin
MET
NSCLC
Note
This fulltext will be available in Jul 2020
Published Date
2019-07-30
Publication Title
Journal of Thoracic Oncology
Volume
volume14
Issue
issue11
Publisher
Elsevier
Start Page
2009
End Page
2018
ISSN
15560864
NCID
AA12058455
Content Type
Journal Article
language
英語
OAI-PMH Set
岡山大学
Copyright Holders
© 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.
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author
PubMed ID
DOI
Related Url
isVersionOf https://doi.org/10.1016/j.jtho.2019.07.017
Citation
Go Makimoto, Kadoaki Ohashi, Shuta Tomida, Kazuya Nishii, Takehiro Matsubara, Hiroe Kayatani, Hisao Higo, Kiichiro Ninomiya, Akiko Sato, Hiromi Watanabe, Hirohisa Kano, Takashi Ninomiya, Toshio Kubo, Kammei Rai, Eiki Ichihara, Katsuyuki Hotta, Masahiro Tabata, Shinichi Toyooka, Minoru Takata, Yoshinobu Maeda, Katsuyuki Kiura, Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden, Journal of Thoracic Oncology, 2019, ISSN 1556-0864, https://doi.org/10.1016/j.jtho.2019.07.017.