PMID- 27783866 OWN - NLM STAT- MEDLINE DCOM- 20170306 LR - 20240324 IS - 1349-7006 (Electronic) IS - 1347-9032 (Print) IS - 1347-9032 (Linking) VI - 108 IP - 1 DP - 2017 Jan TI - Amphiregulin triggered epidermal growth factor receptor activation confers in vivo crizotinib-resistance of EML4-ALK lung cancer and circumvention by epidermal growth factor receptor inhibitors. PG - 53-60 LID - 10.1111/cas.13111 [doi] AB - Crizotinib, a first-generation anaplastic lymphoma kinase (ALK) tyrosine-kinase inhibitor, is known to be effective against echinoderm microtubule-associated protein-like 4 (EML4)-ALK-positive non-small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib-resistant cells (A925LPE3-CR) via long-term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4-ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib-resistant cells, and these cells were cross-resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3-CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine-kinase inhibitor (erlotinib) or an anti-EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4-ALK lung cancer. CI - (c) 2016 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association. FAU - Taniguchi, Hirokazu AU - Taniguchi H AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. AD - Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. FAU - Takeuchi, Shinji AU - Takeuchi S AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. FAU - Fukuda, Koji AU - Fukuda K AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. FAU - Nakagawa, Takayuki AU - Nakagawa T AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. AD - Tsukuba Laboratory, Eisai Co., Ltd, Tsukuba, Japan. FAU - Arai, Sachiko AU - Arai S AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. FAU - Nanjo, Shigeki AU - Nanjo S AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. FAU - Yamada, Tadaaki AU - Yamada T AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. FAU - Yamaguchi, Hiroyuki AU - Yamaguchi H AD - Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. FAU - Mukae, Hiroshi AU - Mukae H AD - Department of Respiratory Medicine, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan. FAU - Yano, Seiji AU - Yano S AD - Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan. LA - eng PT - Journal Article DEP - 20161230 PL - England TA - Cancer Sci JT - Cancer science JID - 101168776 RN - 0 (Amphiregulin) RN - 0 (Cell Cycle Proteins) RN - 0 (Microtubule-Associated Proteins) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrazoles) RN - 0 (Pyridines) RN - 0 (RNA, Small Interfering) RN - 53AH36668S (Crizotinib) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Alk protein, mouse) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Receptor Protein-Tyrosine Kinases) RN - EC 3.4.21.- (EML4 protein, human) RN - EC 3.4.21.- (Serine Endopeptidases) SB - IM MH - Amphiregulin/deficiency/genetics/*metabolism MH - Anaplastic Lymphoma Kinase MH - Animals MH - Carcinoma, Non-Small-Cell Lung/drug therapy/metabolism/pathology MH - Cell Cycle Proteins/*metabolism MH - Cell Line, Tumor MH - Crizotinib MH - Disease Models, Animal MH - Drug Resistance, Neoplasm/*drug effects/genetics MH - ErbB Receptors/*antagonists & inhibitors/genetics/*metabolism MH - Erlotinib Hydrochloride MH - Humans MH - Lung Neoplasms/drug therapy/*metabolism/pathology MH - Male MH - Mice MH - Microtubule-Associated Proteins/*metabolism MH - Mutation MH - Pleural Effusion MH - Pleural Neoplasms MH - Protein Kinase Inhibitors/pharmacology MH - Pyrazoles/*pharmacology MH - Pyridines/*pharmacology MH - RNA, Small Interfering/genetics MH - Receptor Protein-Tyrosine Kinases/*metabolism MH - Serine Endopeptidases/*metabolism MH - Xenograft Model Antitumor Assays PMC - PMC5276841 OTO - NOTNLM OT - Amphiregulin OT - EML4-ALK OT - crizotinib-resistance OT - epidermal growth factor receptor OT - lung cancer EDAT- 2016/10/27 06:00 MHDA- 2017/03/07 06:00 PMCR- 2017/01/01 CRDT- 2016/10/27 06:00 PHST- 2016/07/19 00:00 [received] PHST- 2016/10/17 00:00 [revised] PHST- 2016/10/22 00:00 [accepted] PHST- 2016/10/27 06:00 [pubmed] PHST- 2017/03/07 06:00 [medline] PHST- 2016/10/27 06:00 [entrez] PHST- 2017/01/01 00:00 [pmc-release] AID - CAS13111 [pii] AID - 10.1111/cas.13111 [doi] PST - ppublish SO - Cancer Sci. 2017 Jan;108(1):53-60. doi: 10.1111/cas.13111. Epub 2016 Dec 30.