{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T20:33:23Z","timestamp":1792787603707,"version":"4.5.0"},"reference-count":85,"publisher":"American Society for Clinical Investigation","issue":"24","license":[{"start":{"date-parts":[[2023,12,22]],"date-time":"2023-12-22T00:00:00Z","timestamp":1703203200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"MEXT\/JSPS","award":["JP22K18383"],"award-info":[{"award-number":["JP22K18383"]}]},{"DOI":"10.13039\/100009619","name":"AMED","doi-asserted-by":"crossref","award":["JP23ama221210h0002,JP23ama221201h0002,JP23ck0106795h0001"],"award-info":[{"award-number":["JP23ama221210h0002,JP23ama221201h0002,JP23ck0106795h0001"]}],"id":[{"id":"10.13039\/100009619","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Chugai Foundation for Innovative Drug Discovery Science","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100007412","name":"Nippon Foundation","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100007412","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,12,22]]},"abstract":"<jats:p>\n                    Although tyrosine kinase inhibitor (TKI) therapy shows marked clinical efficacy in patients with anaplastic lymphoma kinase\u2013positive (ALK\n                    <jats:sup>+<\/jats:sup>\n                    ) and ROS proto-oncogene 1\u2013positive (ROS1\n                    <jats:sup>+<\/jats:sup>\n                    ) non\u2013small cell lung cancer (NSCLC), most of these patients eventually relapse with acquired resistance. Therefore, genome-wide CRISPR\/Cas9 knockout screening was performed using an ALK\n                    <jats:sup>+<\/jats:sup>\n                    NSCLC cell line established from pleural effusion without ALK-TKI treatment. After 9 days of ALK-TKI therapy, sequencing analysis was performed, which identified several tumor suppressor genes, such as NF2 or MED12, and multiple candidate genes. Among them, this study focused on ERRFI1, which is known as MIG6 and negatively regulates EGFR signaling. Interestingly, MIG6 loss induced resistance to ALK-TKIs by treatment with quite a low dose of EGF, which is equivalent to plasma concentration, through the upregulation of MAPK and PI3K\/AKT\/mTOR pathways. Combination therapy with ALK-TKIs and anti-EGFR antibodies could overcome the acquired resistance in both in vivo and in vitro models. In addition, this verified that MIG6 loss induces resistance to ROS1-TKIs in ROS1\n                    <jats:sup>+<\/jats:sup>\n                    cell lines. This study found a potentially novel factor that plays a role in ALK and ROS1-TKI resistance by activating the EGFR pathway with low-dose ligands.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.173688","type":"journal-article","created":{"date-parts":[[2023,11,2]],"date-time":"2023-11-02T12:01:17Z","timestamp":1698926477000},"source":"Crossref","is-referenced-by-count":13,"title":["MIG6 loss confers resistance to ALK\/ROS1 inhibitors in NSCLC through EGFR activation by low-dose EGF"],"prefix":"10.1172","volume":"8","author":[{"given":"Nobuyuki","family":"Kondo","sequence":"first","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan."},{"name":"Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takahiro","family":"Utsumi","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan."},{"name":"Department of Respiratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuki","family":"Shimizu","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan."},{"name":"Department of Computational Biology and Medical Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ai","family":"Takemoto","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Oh-hara","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1491-923X","authenticated-orcid":true,"given":"Ken","family":"Uchibori","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medical Oncology, the Cancer Institute Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sophia","family":"Subat-Motoshi","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Cancer Institute Hospital, and"},{"name":"Pathology Project for Molecular Targets, Cancer Institute, JFCR, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hironori","family":"Ninomiya","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Cancer Institute Hospital, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-5800","authenticated-orcid":true,"given":"Kengo","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Department of Pathology, the Cancer Institute Hospital, and"},{"name":"Pathology Project for Molecular Targets, Cancer Institute, JFCR, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4969-4165","authenticated-orcid":true,"given":"Makoto","family":"Nishio","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medical Oncology, the Cancer Institute Hospital,"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-9815","authenticated-orcid":true,"given":"Yasunari","family":"Miyazaki","sequence":"additional","affiliation":[{"name":"Department of Respiratory Medicine, Tokyo Medical and Dental University, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7394-895X","authenticated-orcid":true,"given":"Ryohei","family":"Katayama","sequence":"additional","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research (JFCR), Tokyo, Japan."},{"name":"Department of Computational Biology and Medical Science, Graduate School of Frontier Science, The University of Tokyo, Tokyo, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"232","published-online":{"date-parts":[[2023,12,22]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2021.6987"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1038\/nature05945"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.44.5353"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-10-0851"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/imj.14435"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2291"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1038\/nm1249"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.04.478"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2027187"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-16-0596"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1256"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1508887"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-21396-w"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-19-1104"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2015.12.105"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2015.12.009"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.3892\/ijo.2014.2797"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-0392"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-021-00250-8"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003316"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3667"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-15-0084"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13236003"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254721"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3930"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.05.019"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2012.10.035"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1340"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1001\/jama.2019.3241"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.12899"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.35.6345"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz131"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2017.75.5587"},{"issue":"2017","key":"B34","article-title":"Patterns of metastatic spread and mechanisms of resistance to crizotinib in ROS1-positive non-small-cell lung cancer","author":"Gainor","year":"2017","journal-title":"JCO Precis Oncol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1111\/1759-7714.14656"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-17-2452"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0082236"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.ctarc.2021.100377"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12789"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2010.02.027"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-08074-0"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-05626-2"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13771-5"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1038\/nature24297"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.07.017"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4040"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1126\/science.1231143"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.1126\/science.1247005"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.50223"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1002\/1878-0261.12853"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-022-00260-0"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2017.016"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0554-4"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1038\/nature11249"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4172\/2155-9929.1000402"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.3892\/mco.2021.2413"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2015.05.010"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(17)30680-0"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(19)30655-2"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11496-z"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1038\/nsmb.3074"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1038\/nature05998"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-14-0750"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1016\/j.lungcan.2017.08.001"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0914930107"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.15252\/embr.202050781"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-020-07057-z"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1186\/s12885-018-4514-3"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.803338"},{"key":"B70","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0211212"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1186\/s40064-015-0891-0"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-48-4-667"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1210\/edrv-11-3-418"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-023-00350-7"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2972"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-2558"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209790"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-17-1226"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.875313"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.04.014"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0264-7"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1038\/s41388-019-0887-2"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.112570"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2018.05.031"},{"key":"B85","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms14768"}],"container-title":["JCI Insight"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/insight.jci.org\/articles\/view\/173688\/files\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T21:45:01Z","timestamp":1779140701000},"score":1,"resource":{"primary":{"URL":"https:\/\/insight.jci.org\/articles\/view\/173688"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,12,22]]},"references-count":85,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2023,12,22]]},"published-print":{"date-parts":[[2023,12,22]]}},"alternative-id":["10.1172\/jci.insight.173688"],"URL":"https:\/\/doi.org\/10.1172\/jci.insight.173688","relation":{},"ISSN":["2379-3708"],"issn-type":[{"value":"2379-3708","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,12,22]]},"article-number":"e173688"}}