{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T12:46:34Z","timestamp":1790858794004,"version":"4.1.0"},"reference-count":56,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2025,11,5]],"date-time":"2025-11-05T00:00:00Z","timestamp":1762300800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/100007038","name":"Lung Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007038","name":"Lung Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007038","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["febs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Molecular Oncology"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>\n                    Rearranged during transfection (\n                    <jats:italic>RET<\/jats:italic>\n                    ) fusions drive subsets of non\u2010small cell lung cancer (NSCLC) and papillary thyroid carcinoma (PTC). Despite new selective RET tyrosine kinase inhibitors (TKIs), resistance usually occurs and is often driven by\n                    <jats:italic>RET<\/jats:italic>\n                    \u2010independent bypass mechanisms. Previous studies have implied crosstalk between RET and proto\u2010oncogene tyrosine\u2010protein kinase SRC, but the anticancer effects of targeting SRC combined with selective RET TKIs, and the underlying molecular mechanisms involved, are not fully understood. Our results show that the multitargeted SRC TKI dasatinib significantly enhanced the efficacy of RET TKIs in\n                    <jats:italic>RET<\/jats:italic>\n                    fusion\u2010positive (\n                    <jats:italic>RET<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    ) NSCLC and PTC cells. Genetic rescue experiments validated that the combination effects between RET TKIs and dasatinib were indeed SRC\u2010dependent. Phosphoproteomics analysis and validation using selective inhibitors and small interfering RNAs (siRNAs) determined that synergy was primarily mediated by suppression of downstream serine\/threonine\u2010protein kinase PAK signaling, with contributions from AKT and ribosomal protein S6. Importantly, synergy was also observed with eCF506 (NXP900), a next\u2010generation clinical SRC inhibitor. Finally, both SRC TKIs restored sensitivity in selpercatinib\u2010resistant\n                    <jats:italic>RET<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    PTC cells. These results elucidate RET and SRC signaling crosstalk in\n                    <jats:italic>RET<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    NSCLC and PTC, suggesting that co\u2010inhibiting SRC has clinical potential in TKI\u2010na\u00efve and \u2010resistant\n                    <jats:italic>RET<\/jats:italic>\n                    <jats:sup>+<\/jats:sup>\n                    cancers.\n                  <\/jats:p>","DOI":"10.1002\/1878-0261.70155","type":"journal-article","created":{"date-parts":[[2025,11,6]],"date-time":"2025-11-06T07:40:54Z","timestamp":1762414854000},"page":"1041-1060","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Dual targeting of\n                    <scp>RET<\/scp>\n                    and\n                    <scp>SRC<\/scp>\n                    synergizes in\n                    <scp>\n                      <i>RET<\/i>\n                    <\/scp>\n                    fusion\u2010positive cancer cells"],"prefix":"10.1002","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4774-4588","authenticated-orcid":false,"given":"Juhyeon","family":"Son","sequence":"first","affiliation":[{"name":"Department of Drug Discovery H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"},{"name":"Cancer Biology PhD Program University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lily L.","family":"Remsing Rix","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bin","family":"Fang","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomics Core H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric A.","family":"Welsh","sequence":"additional","affiliation":[{"name":"Biostatistics and Bioinformatics Shared Resource H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicole V.","family":"Bremer","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami  FL USA"},{"name":"Sylvester Comprehensive Cancer Center (SCCC)  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Foglizzo","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami  FL USA"},{"name":"Sylvester Comprehensive Cancer Center (SCCC)  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Roa","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami  FL USA"},{"name":"Sylvester Comprehensive Cancer Center (SCCC)  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nickole","family":"Sigcha\u2010Coello","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami  FL USA"},{"name":"Sylvester Comprehensive Cancer Center (SCCC)  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric B.","family":"Haura","sequence":"additional","affiliation":[{"name":"Department of Thoracic Oncology H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexander","family":"Drilon","sequence":"additional","affiliation":[{"name":"Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan Kettering Cancer Center Weill Cornell Medical College  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Koomen","sequence":"additional","affiliation":[{"name":"Department of Molecular Oncology H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"},{"name":"Department of Oncologic Sciences University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1397-2656","authenticated-orcid":false,"given":"Emiliano","family":"Cocco","sequence":"additional","affiliation":[{"name":"Department of Biochemistry and Molecular Biology Miller School of Medicine, University of Miami  FL USA"},{"name":"Sylvester Comprehensive Cancer Center (SCCC)  Miami FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8242-2770","authenticated-orcid":false,"given":"Uwe","family":"Rix","sequence":"additional","affiliation":[{"name":"Department of Drug Discovery H. Lee Moffitt Cancer Center &amp; Research Institute  Tampa FL USA"},{"name":"Department of Oncologic Sciences University of South Florida  Tampa FL USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,11,5]]},"reference":[{"key":"e_1_2_11_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3680"},{"key":"e_1_2_11_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/genes11040424"},{"key":"e_1_2_11_4_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2022.932353"},{"key":"e_1_2_11_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.09.050"},{"key":"e_1_2_11_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41571\u2010023\u201000733\u20106"},{"key":"e_1_2_11_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41698\u2010023\u201000347\u20102"},{"key":"e_1_2_11_8_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470\u20102045(21)00247\u20103"},{"key":"e_1_2_11_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2213\u20108587(21)00120\u20100"},{"key":"e_1_2_11_10_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2309457"},{"key":"e_1_2_11_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2020.09.015"},{"key":"e_1_2_11_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467\u2010022\u201028848\u2010x"},{"key":"e_1_2_11_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2020.01.006"},{"key":"e_1_2_11_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/s43018\u2010023\u201000630\u2010y"},{"key":"e_1_2_11_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrclinonc.2009.129"},{"key":"e_1_2_11_16_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M211426200"},{"key":"e_1_2_11_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/nm.2309"},{"key":"e_1_2_11_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.scr.2014.09.007"},{"key":"e_1_2_11_19_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2009\u20100009"},{"key":"e_1_2_11_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1254721"},{"key":"e_1_2_11_21_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drup.2024.101081"},{"key":"e_1_2_11_22_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.chembiol.2023.09.011"},{"key":"e_1_2_11_23_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535-7163.MCT-17-0351"},{"key":"e_1_2_11_24_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2014\u20100228"},{"key":"e_1_2_11_25_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2009.25.4029"},{"key":"e_1_2_11_26_1","doi-asserted-by":"publisher","DOI":"10.1158\/1535\u20107163.MCT\u201015\u20100350"},{"key":"e_1_2_11_27_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201011\u20103359"},{"key":"e_1_2_11_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.08.037"},{"key":"e_1_2_11_29_1","doi-asserted-by":"publisher","DOI":"10.1124\/molpharm.120.000207"},{"key":"e_1_2_11_30_1","doi-asserted-by":"publisher","DOI":"10.1530\/ERC\u201013\u20100085"},{"key":"e_1_2_11_31_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1511"},{"key":"e_1_2_11_32_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471\u20102105\u201014\u2010153"},{"key":"e_1_2_11_33_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac963"},{"key":"e_1_2_11_34_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac194"},{"key":"e_1_2_11_35_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1000"},{"key":"e_1_2_11_36_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.1239303"},{"key":"e_1_2_11_37_1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btq596"},{"key":"e_1_2_11_38_1","doi-asserted-by":"publisher","DOI":"10.1038\/nbt.1513"},{"key":"e_1_2_11_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.canlet.2024.217220"},{"key":"e_1_2_11_40_1","doi-asserted-by":"publisher","DOI":"10.1038\/nchembio.332"},{"key":"e_1_2_11_41_1","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20132496"},{"key":"e_1_2_11_42_1","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00533\u201013"},{"key":"e_1_2_11_43_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1538\u20107836.2012.04814.x"},{"key":"e_1_2_11_44_1","doi-asserted-by":"publisher","DOI":"10.1101\/gad.8.17.1999"},{"key":"e_1_2_11_45_1","doi-asserted-by":"publisher","DOI":"10.1016\/s0960\u20109822(99)80453\u20109"},{"key":"e_1_2_11_46_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.24.13738"},{"key":"e_1_2_11_47_1","doi-asserted-by":"publisher","DOI":"10.1186\/gb\u20102007\u20108\u20109\u2010r183"},{"key":"e_1_2_11_48_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3645"},{"key":"e_1_2_11_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2013.11.013"},{"key":"e_1_2_11_50_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2007.03.003"},{"key":"e_1_2_11_51_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncb1795"},{"key":"e_1_2_11_52_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008\u20105472.CAN\u201021\u20100613"},{"key":"e_1_2_11_53_1","doi-asserted-by":"publisher","DOI":"10.1002\/cncr.30135"},{"key":"e_1_2_11_54_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M117.808063"},{"key":"e_1_2_11_55_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078\u20100432.CCR\u201024\u20101762"},{"key":"e_1_2_11_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.956220"},{"key":"e_1_2_11_57_1","doi-asserted-by":"publisher","DOI":"10.1158\/2767\u20109764.crc\u201022\u20100303"}],"container-title":["Molecular Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70155","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/1878-0261.70155","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/1878-0261.70155","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T16:13:36Z","timestamp":1775664816000},"score":1,"resource":{"primary":{"URL":"https:\/\/febs.onlinelibrary.wiley.com\/doi\/10.1002\/1878-0261.70155"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,5]]},"references-count":56,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2026,4]]}},"alternative-id":["10.1002\/1878-0261.70155"],"URL":"https:\/\/doi.org\/10.1002\/1878-0261.70155","archive":["Portico"],"relation":{"has-review":[{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v1\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v2\/review1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v1\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v2\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v3\/decision1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v3\/response1","asserted-by":"object"},{"id-type":"doi","id":"10.1002\/1878-0261.70155\/v2\/decision1","asserted-by":"object"}]},"ISSN":["1574-7891","1878-0261"],"issn-type":[{"value":"1574-7891","type":"print"},{"value":"1878-0261","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,5]]},"assertion":[{"value":"2025-05-15","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-10-22","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-11-05","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}