Rapid Acquisition of Alectinib Resistance in ALK-Positive Lung Cancer With High Tumor Mutation Burden.

Autor:	Makimoto G; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Ohashi K; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan. Electronic address: kohashi@cc.okayama-u.ac.jp., Tomida S; Okayama University Hospital Biobank, Okayama University Hospital, Okayama, Japan., Nishii K; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Matsubara T; Okayama University Hospital Biobank, Okayama University Hospital, Okayama, Japan., Kayatani H; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Higo H; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Ninomiya K; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Sato A; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan., Watanabe H; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Kano H; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Ninomiya T; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan., Kubo T; Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan., Rai K; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan., Ichihara E; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan., Hotta K; Center of Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan., Tabata M; Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan., Toyooka S; Okayama University Hospital Biobank, Okayama University Hospital, Okayama, Japan; Department of Thoracic Surgery, Okayama University Hospital, Okayama, Japan., Takata M; Laboratory of DNA Damage Signaling, Department of Late Effects Studies, Graduate School of Biostudies, Radiation Biology Center, Kyoto University, Yoshidakonoe-cho, Sakyo-ku, Kyoto, Japan., Maeda Y; Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan., Kiura K; Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.
Jazyk:	angličtina
Zdroj:	Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer [J Thorac Oncol] 2019 Nov; Vol. 14 (11), pp. 2009-2018. Date of Electronic Publication: 2019 Jul 30.
DOI:	10.1016/j.jtho.2019.07.017
Abstrakt:	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. (Copyright © 2019 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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