PMID- 31972351 OWN - NLM STAT- MEDLINE DCOM- 20210106 LR - 20220603 IS - 1556-1380 (Electronic) IS - 1556-0864 (Linking) VI - 15 IP - 5 DP - 2020 May TI - Osimertinib Overcomes Alectinib Resistance Caused by Amphiregulin in a Leptomeningeal Carcinomatosis Model of ALK-Rearranged Lung Cancer. PG - 752-765 LID - S1556-0864(20)30022-8 [pii] LID - 10.1016/j.jtho.2020.01.001 [doi] AB - INTRODUCTION: Leptomeningeal carcinomatosis (LMC) occurs frequently in anaplastic lymphoma kinase (ALK)-rearranged NSCLC and develops acquired resistance to ALK tyrosine kinase inhibitors (ALK TKIs). This study aimed to clarify the resistance mechanism to alectinib, a second-generation ALK TKI, in LMC and test a novel therapeutic strategy. METHODS: We induced alectinib resistance in an LMC mouse model with ALK-rearranged NSCLC cell line, A925LPE3, by continuous oral alectinib treatment, established A925L/AR cells. Resistance mechanisms were analyzed using several assays, including Western blot and receptor tyrosine kinase array. We also measured amphiregulin (AREG) concentrations in cerebrospinal fluid from patients with ALK-rearranged NSCLC with alectinib-refractory LMC by enzyme-linked immunosorbent assay. RESULTS: A925L/AR cells were moderately resistant to various ALK TKIs, such as alectinib, crizotinib, ceritinib, and lorlatinib, compared with parental cells in vitro. A925L/AR cells acquired the resistance by EGFR activation resulting from AREG overexpression caused by decreased expression of microRNA-449a. EGFR TKIs and anti-EGFR antibody resensitized A925L/AR cells to alectinib in vitro. In the LMC model with A925L/AR cells, combined treatment with alectinib and EGFR TKIs, such as erlotinib and osimertinib, successfully controlled progression of LMC. Mass spectrometry imaging showed accumulation of the EGFR TKIs in the tumor lesions. Moreover, notably higher AREG levels were detected in cerebrospinal fluid of patients with alectinib-resistant ALK-rearranged NSCLC with LMC (n = 4), compared with patients with EGFR-mutated NSCLC with EGFR TKI-resistant LMC (n = 30), or patients without LMC (n = 24). CONCLUSIONS: These findings indicate the potential of novel therapies targeting both ALK and EGFR for the treatment of ALK TKI-resistant LMC in ALK-rearranged NSCLC. CI - Copyright (c) 2020 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved. FAU - Arai, Sachiko AU - Arai S AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan. FAU - Takeuchi, Shinji AU - Takeuchi S AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa University, Kanazawa, Japan. FAU - Fukuda, Koji AU - Fukuda K AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa University, Kanazawa, Japan. FAU - Taniguchi, Hirokazu AU - Taniguchi H AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Department of Respiratory Medicine, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan. FAU - Nishiyama, Akihiro AU - Nishiyama A AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan. FAU - Tanimoto, Azusa AU - Tanimoto A AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan. FAU - Satouchi, Miyako AU - Satouchi M AD - Department of Thoracic Oncology, Hyogo Cancer Center, Akashi, Japan. FAU - Yamashita, Kaname AU - Yamashita K AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan. FAU - Ohtsubo, Koshiro AU - Ohtsubo K AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan. FAU - Nanjo, Shigeki AU - Nanjo S AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Department of Medicine, Division of Hematology-Oncology, University of California San Francisco, San Francisco, California; Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan. FAU - Kumagai, Toru AU - Kumagai T AD - Department of Thoracic Oncology, Osaka International Cancer Institute, Osaka, Japan. FAU - Katayama, Ryohei AU - Katayama R AD - Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, Japan. FAU - Nishio, Makoto AU - Nishio M AD - Department of Thoracic Medical Oncology, The Cancer Institute Hospital, Japanese Foundation For Cancer Research, Tokyo, Japan. FAU - Zheng, Mei-Mei AU - Zheng MM AD - Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangzhou, People's Republic of China; Guangdong Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China. FAU - Wu, Yi-Long AU - Wu YL AD - Guangdong Lung Cancer Institute, Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, Guangzhou, People's Republic of China; Guangdong Hospital and Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China; Guangdong Hospital, School of Medicine, South China University of Technology, Guangzhou, People's Republic of China. FAU - Nishihara, Hiroshi AU - Nishihara H AD - Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan. FAU - Yamamoto, Takushi AU - Yamamoto T AD - Analytical and Measuring Instruments Division, Global Application Development Center, Shimadzu Corporation, Kyoto, Japan. FAU - Nakada, Mitsutoshi AU - Nakada M AD - Department of Neurosurgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Japan. FAU - Yano, Seiji AU - Yano S AD - Division of Medical Oncology, Kanazawa University Cancer Research Institute, Kanazawa, Japan; Nano Life Science Institute, Kanazawa University, Kanazawa University, Kanazawa, Japan. Electronic address: syano@staff.kanazawa-u.ac.jp. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200121 PL - United States TA - J Thorac Oncol JT - Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer JID - 101274235 RN - 0 (Acrylamides) RN - 0 (Amphiregulin) RN - 0 (Aniline Compounds) RN - 0 (Carbazoles) RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - 3C06JJ0Z2O (osimertinib) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - LIJ4CT1Z3Y (alectinib) SB - IM CIN - J Thorac Oncol. 2020 Jun;15(6):e92-e93. PMID: 32471569 CIN - J Thorac Oncol. 2020 Jun;15(6):e93. PMID: 32471570 MH - Acrylamides MH - Amphiregulin/genetics MH - Anaplastic Lymphoma Kinase/genetics MH - Aniline Compounds MH - Animals MH - Carbazoles MH - Cell Line, Tumor MH - Drug Resistance, Neoplasm MH - ErbB Receptors/genetics MH - Humans MH - *Lung Neoplasms/drug therapy/genetics MH - *Meningeal Carcinomatosis MH - Mice MH - Piperidines MH - Protein Kinase Inhibitors/pharmacology MH - Receptor Protein-Tyrosine Kinases/genetics OTO - NOTNLM OT - Alectinib resistance OT - EML4-ALK OT - Leptomeningeal metastasis OT - Osimertinib EDAT- 2020/01/24 06:00 MHDA- 2021/01/07 06:00 CRDT- 2020/01/24 06:00 PHST- 2019/10/09 00:00 [received] PHST- 2020/01/06 00:00 [revised] PHST- 2020/01/09 00:00 [accepted] PHST- 2020/01/24 06:00 [pubmed] PHST- 2021/01/07 06:00 [medline] PHST- 2020/01/24 06:00 [entrez] AID - S1556-0864(20)30022-8 [pii] AID - 10.1016/j.jtho.2020.01.001 [doi] PST - ppublish SO - J Thorac Oncol. 2020 May;15(5):752-765. doi: 10.1016/j.jtho.2020.01.001. Epub 2020 Jan 21.