{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,9]],"date-time":"2026-10-09T21:38:15Z","timestamp":1791581895126,"version":"4.3.4"},"reference-count":61,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2022,9,13]],"date-time":"2022-09-13T00:00:00Z","timestamp":1663027200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100009270","name":"Bonnie J. Addario Lung Cancer Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100009270","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Thoracic Cancer"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>ROS1 tyrosine kinase inhibitors (TKIs) have demonstrated significant clinical benefit for ROS1+ NSCLC patients. However, TKI resistance inevitably develops through ROS1 kinase domain (KD) modification or another kinase driving bypass signaling. While multiple TKIs have been designed to target <jats:italic>ROS1<\/jats:italic> KD mutations, less is known about bypass signaling in TKI\u2010resistant ROS1+ lung cancers.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Utilizing a primary, patient\u2010derived <jats:italic>TPM3\u2010ROS1<\/jats:italic> cell line (CUTO28), we derived an entrectinib\u2010resistant line (CUTO28\u2010ER). We evaluated proliferation and signaling responses to TKIs, and utilized RNA sequencing, whole exome sequencing, and fluorescence in situ hybridization to detect transcriptional, mutational, and copy number alterations, respectively. We substantiated in vitro findings using a <jats:italic>CD74\u2010ROS1<\/jats:italic> NSCLC patient's tumor samples. Last, we analyzed circulating tumor DNA (ctDNA) from ROS1+ NSCLC patients in the STARTRK\u20102 entrectinib trial to determine the prevalence of <jats:italic>MET<\/jats:italic> amplification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>CUTO28\u2010ER cells did not exhibit <jats:italic>ROS1<\/jats:italic> KD mutations. MET TKIs inhibited proliferation and downstream signaling and <jats:italic>MET<\/jats:italic> transcription was elevated in CUTO28\u2010ER cells. CUTO28\u2010ER cells displayed extrachromosomal (ecDNA) <jats:italic>MET<\/jats:italic> amplification without <jats:italic>MET<\/jats:italic> activating mutations, exon 14 skipping, or fusions. The <jats:italic>CD74\u2010ROS1<\/jats:italic> patient samples illustrated <jats:italic>MET<\/jats:italic> amplification while receiving ROS1 TKI. Finally, two of 105 (1.9%) entrectinib\u2010resistant ROS1+ NSCLC STARTRK\u20102 patients with ctDNA analysis at enrollment and disease progression displayed <jats:italic>MET<\/jats:italic> amplification.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Treatment with ROS1\u2010selective inhibitors may lead to MET\u2010mediated resistance. The discovery of ecDNA <jats:italic>MET<\/jats:italic> amplification is noteworthy, as ecDNA is associated with more aggressive cancers. Following progression on ROS1\u2010selective inhibitors, <jats:italic>MET<\/jats:italic> gene testing and treatments targeting MET should be explored to overcome MET\u2010driven resistance.<\/jats:p><\/jats:sec>","DOI":"10.1111\/1759-7714.14656","type":"journal-article","created":{"date-parts":[[2022,9,14]],"date-time":"2022-09-14T05:59:40Z","timestamp":1663135180000},"page":"3032-3041","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["<scp><i>MET<\/i><\/scp> gene amplification is a mechanism of resistance to entrectinib in <scp>ROS1<\/scp>+ <scp>NSCLC<\/scp>"],"prefix":"10.1111","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4446-2253","authenticated-orcid":false,"given":"Logan C.","family":"Tyler","sequence":"first","affiliation":[{"name":"Department of Medicine\u2014Division of Medical Oncology University of Colorado\u2014Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anh T.","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Medicine\u2014Division of Medical Oncology University of Colorado\u2014Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nan","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Medicine\u2014Division of Medical Oncology University of Colorado\u2014Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hala","family":"Nijmeh","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado\u2014Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liming","family":"Bao","sequence":"additional","affiliation":[{"name":"Department of Pathology University of Colorado\u2014Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy R.","family":"Wilson","sequence":"additional","affiliation":[{"name":"Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Chen","sequence":"additional","affiliation":[{"name":"Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Simmons","sequence":"additional","affiliation":[{"name":"Genentech, Inc.  South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristen M.","family":"Turner","sequence":"additional","affiliation":[{"name":"Boundless Bio, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dean","family":"Perusse","sequence":"additional","affiliation":[{"name":"Boundless Bio, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shailaja","family":"Kasibhatla","sequence":"additional","affiliation":[{"name":"Boundless Bio, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Christiansen","sequence":"additional","affiliation":[{"name":"Boundless Bio, Inc.  San Diego California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arkadiusz Z.","family":"Dudek","sequence":"additional","affiliation":[{"name":"HealthPartners Cancer Center at Regions Hospital  St. Paul Minnesota USA"},{"name":"Department of Medicine\u2014Division of Hematology, Oncology and Transplantation University of Minnesota  Minneapolis Minnesota USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert C.","family":"Doebele","sequence":"additional","affiliation":[{"name":"Department of Medicine\u2014Division of Medical Oncology University of Colorado\u2014Anschutz Medical Campus  Aurora Colorado USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2022,9,13]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.6.8.3000"},{"issue":"9","key":"e_1_2_6_3_1","first-page":"3109","article-title":"Characterization of an activated human ros 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