{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T04:43:46Z","timestamp":1789101826471,"version":"build-2803163510"},"reference-count":77,"publisher":"National Academy of Sciences","issue":"39","license":[{"start":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T00:00:00Z","timestamp":1441670400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.pnas.org\/site\/misc\/userlicense.xhtml"}],"funder":[{"DOI":"10.13039\/100000011","name":"Howard Hughes Medical Institute","doi-asserted-by":"publisher","award":["No # assigned"],"award-info":[{"award-number":["No # assigned"]}],"id":[{"id":"10.13039\/100000011","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["R37CA065823"],"award-info":[{"award-number":["R37CA065823"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["HL082978-01"],"award-info":[{"award-number":["HL082978-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["CA049639-23"],"award-info":[{"award-number":["CA049639-23"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["CA178397-01"],"award-info":[{"award-number":["CA178397-01"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2015,9,29]]},"abstract":"<jats:title>Significance<\/jats:title>\n                  <jats:p>\n                    Targeting oncogenic ROS1 fusion proteins with crizotinib has shown promising clinical outcomes in non-small cell lung cancer (NSCLC) patients, but emergence of resistance to therapy has been reported. By profiling the activity of clinically viable ROS1\/anaplastic lymphoma kinase (ALK) inhibitors, we discovered that the Food and Drug Administration (FDA)-approved inhibitor cabozantinib potently inhibits native ROS1 and the crizotinib-resistant ROS1\n                    <jats:sup>G2032R<\/jats:sup>\n                    mutant, suggesting potential utility for treatment of ROS1-rearranged lung cancer. Notably, cabozantinib is ineffective against the closely related ALK kinase. Molecular modeling shows specific structural differences between the kinase domains of ROS1 and ALK that explain selective binding of cabozantinib to ROS1. These findings reveal limitations pertaining to the widely presumed inhibitory reciprocity of ROS1 and ALK inhibitors and may facilitate rational design of new ROS1-selective inhibitors.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1515281112","type":"journal-article","created":{"date-parts":[[2015,9,8]],"date-time":"2015-09-08T22:21:21Z","timestamp":1441750881000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":103,"title":["Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors"],"prefix":"10.1073","volume":"112","author":[{"given":"Monika A.","family":"Davare","sequence":"first","affiliation":[{"name":"Knight Cancer Institute, Oregon Health &amp; Science University, Portland, OR 97239;"},{"name":"Department of Pediatrics, Oregon Health &amp; Science University, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nadeem A.","family":"Vellore","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112;"},{"name":"Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT 84112;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob P.","family":"Wagner","sequence":"additional","affiliation":[{"name":"Knight Cancer Institute, Oregon Health &amp; Science University, Portland, OR 97239;"},{"name":"Department of Pediatrics, Oregon Health &amp; Science University, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher A.","family":"Eide","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health &amp; Science University, Portland, OR 97239;"},{"name":"Howard Hughes Medical Institute, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James R.","family":"Goodman","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health &amp; Science University, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Drilon","sequence":"additional","affiliation":[{"name":"Memorial Sloan Kettering Cancer Center, New York, NY 10065"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael W.","family":"Deininger","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112;"},{"name":"Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT 84112;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"O\u2019Hare","sequence":"additional","affiliation":[{"name":"Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT 84112;"},{"name":"Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT 84112;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian J.","family":"Druker","sequence":"additional","affiliation":[{"name":"Division of Hematology and Medical Oncology, Knight Cancer Institute, Oregon Health &amp; Science University, Portland, OR 97239;"},{"name":"Howard Hughes Medical Institute, Portland, OR 97239;"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2015,9,8]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm1009-1149"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa062867"},{"key":"e_1_3_3_3_2","first-page":"85","article-title":"Chromosome studies on normal and leukemic human leukocytes","volume":"25","author":"Nowell PC","year":"1960","unstructured":"PC Nowell, DA Hungerford, Chromosome studies on normal and leukemic human leukocytes. J Natl Cancer Inst 25, 85\u2013109 (1960).","journal-title":"J Natl Cancer Inst"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3612"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-10-0615"},{"key":"e_1_3_3_6_2","first-page":"429","article-title":"ALK inhibitors in non-small cell lung cancer: Crizotinib and beyond","volume":"12","author":"Awad MM","year":"2014","unstructured":"MM Awad, AT Shaw, ALK inhibitors in non-small cell lung cancer: Crizotinib and beyond. Clin Adv Hematol Oncol 12, 429\u2013439 (2014).","journal-title":"Clin Adv Hematol Oncol"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2012.44.5353"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-12-2851"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0056010"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-06-1193"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1311707110"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2011.35.6345"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0b013e31826baf83"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1214886"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1406766"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-09-3314"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-2437"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-06-0658"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-2906"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-11-1648"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3003728"},{"key":"e_1_3_3_22_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1215530"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1319583110"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-physchem-040412-110047"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-biophys-042910-155245"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF01891978"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp3009699"},{"key":"e_1_3_3_28_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp972113j"},{"key":"e_1_3_3_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bpc.2013.10.007"},{"key":"e_1_3_3_30_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10822-007-9159-2"},{"key":"e_1_3_3_31_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm990401t"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.2174\/092986711795328382"},{"key":"e_1_3_3_33_2","doi-asserted-by":"publisher","DOI":"10.1111\/cbdd.12198"},{"key":"e_1_3_3_34_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-08-4889"},{"key":"e_1_3_3_35_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm061381f"},{"key":"e_1_3_3_36_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409792200"},{"key":"e_1_3_3_37_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2014.104"},{"key":"e_1_3_3_38_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1007478"},{"key":"e_1_3_3_39_2","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3388"},{"key":"e_1_3_3_40_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-0259"},{"key":"e_1_3_3_41_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI30890"},{"key":"e_1_3_3_42_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2013-03-487728"},{"key":"e_1_3_3_43_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.07.006"},{"key":"e_1_3_3_44_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0040144"},{"key":"e_1_3_3_45_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0811223106"},{"key":"e_1_3_3_46_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(00)80356-1"},{"key":"e_1_3_3_47_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2947"},{"key":"e_1_3_3_48_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(14)70362-6"},{"key":"e_1_3_3_49_2","doi-asserted-by":"publisher","DOI":"10.1097\/JTO.0000000000000455"},{"key":"e_1_3_3_50_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1311107"},{"key":"e_1_3_3_51_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm2007613"},{"key":"e_1_3_3_52_2","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-13-0846"},{"key":"e_1_3_3_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2011.04.004"},{"key":"e_1_3_3_54_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1511"},{"key":"e_1_3_3_55_2","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1990"},{"key":"e_1_3_3_56_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1823"},{"key":"e_1_3_3_57_2","doi-asserted-by":"publisher","DOI":"10.1021\/cb500129t"},{"key":"e_1_3_3_58_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-3879"},{"key":"e_1_3_3_59_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-14-1385"},{"key":"e_1_3_3_60_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2006-02-004580"},{"key":"e_1_3_3_61_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2009.09.028"},{"key":"e_1_3_3_62_2","doi-asserted-by":"publisher","DOI":"10.1038\/nature11016"},{"key":"e_1_3_3_63_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M112.391425"},{"key":"e_1_3_3_64_2","doi-asserted-by":"publisher","DOI":"10.1002\/pst.426"},{"key":"e_1_3_3_65_2","volume-title":"AMBER 12","author":"Case DA","year":"2012","unstructured":"DA Case, AMBER 12 (University of California, San Fransisco, 2012)."},{"key":"e_1_3_3_66_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20289"},{"key":"e_1_3_3_67_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.540130805"},{"key":"e_1_3_3_68_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.464397"},{"key":"e_1_3_3_69_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.467468"},{"key":"e_1_3_3_70_2","doi-asserted-by":"publisher","DOI":"10.1080\/00268978800101881"},{"key":"e_1_3_3_71_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct400341p"},{"key":"e_1_3_3_72_2","doi-asserted-by":"publisher","DOI":"10.1021\/ct500381c"},{"key":"e_1_3_3_73_2","doi-asserted-by":"publisher","DOI":"10.1021\/jm051256o"},{"key":"e_1_3_3_74_2","doi-asserted-by":"publisher","DOI":"10.1002\/jcc.20035"},{"key":"e_1_3_3_75_2","doi-asserted-by":"publisher","DOI":"10.1021\/j100142a004"},{"key":"e_1_3_3_76_2","doi-asserted-by":"publisher","DOI":"10.1063\/1.445869"},{"key":"e_1_3_3_77_2","doi-asserted-by":"publisher","DOI":"10.1021\/jp8001614"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.pnas.org\/syndication\/doi\/10.1073\/pnas.1515281112","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.1515281112","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,12]],"date-time":"2022-04-12T23:58:11Z","timestamp":1649807891000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.1515281112"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2015,9,8]]},"references-count":77,"journal-issue":{"issue":"39","published-print":{"date-parts":[[2015,9,29]]}},"alternative-id":["10.1073\/pnas.1515281112"],"URL":"https:\/\/doi.org\/10.1073\/pnas.1515281112","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2015,9,8]]},"assertion":[{"value":"2015-09-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}