{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,30]],"date-time":"2025-11-30T09:13:16Z","timestamp":1764493996391,"version":"3.37.3"},"reference-count":59,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,7,17]],"date-time":"2017-07-17T00:00:00Z","timestamp":1500249600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,7,17]],"date-time":"2017-07-17T00:00:00Z","timestamp":1500249600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p><jats:italic>ROS1<\/jats:italic> rearrangement is observed in 1\u20132% of non-small cell lung cancers (NSCLC). The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has induced marked tumour shrinkage in <jats:italic>ROS1<\/jats:italic>-rearranged cancers. However, emergence of acquired resistance to TKI is inevitable within a few years. Previous findings indicate that cabozantinib overcomes secondary mutation\u2013mediated crizotinib-resistance in <jats:italic>ROS1<\/jats:italic>-fusion-positive cells. Here we attempted to establish cabozantinib-resistant cells by <jats:italic>N<\/jats:italic>-ethyl-<jats:italic>N<\/jats:italic>-nitrosourea mutagenesis screening using CD74-ROS1\u2013expressing Ba\/F3 cells. Two resistant cell lines with CD74-ROS1 F2004V or F2075C mutations, which are homologous to ALK F1174 or F1245 mutations, survived in the presence of a low dose of ROS1-TKI. Removal of ROS1-TKI from these TKI-addicted cells induced excessive activation of ROS1 tyrosine kinase followed by apoptosis. We succeeded in recapturing the TKI-addicted phenotype using doxycycline-inducible CD74-ROS1 mutant over-expression in Ba\/F3 cells, suggesting that excessive <jats:italic>ROS1<\/jats:italic> oncogenic signaling itself induced apoptosis instead of cell growth. Phosphoproteomic analysis and high-throughput inhibitor screening revealed that excessive ROS1 signaling in the TKI-addicted cells phosphorylated or activated apoptosis-related molecules such as FAF1 or p38. Collectively, our findings partly clarify molecular mechanisms of excessive <jats:italic>ROS1<\/jats:italic> oncogenic signaling that mediates paradoxical induction of apoptosis.<\/jats:p>","DOI":"10.1038\/s41598-017-05736-9","type":"journal-article","created":{"date-parts":[[2017,7,10]],"date-time":"2017-07-10T17:13:23Z","timestamp":1499706803000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["TKI-addicted ROS1-rearranged cells are destined to survival or death by the intensity of ROS1 kinase activity"],"prefix":"10.1038","volume":"7","author":[{"given":"Hayato","family":"Ogura","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuka","family":"Nagatake-Kobayashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jun","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takeshi","family":"Tomonaga","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naoya","family":"Fujita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7394-895X","authenticated-orcid":false,"given":"Ryohei","family":"Katayama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,7,17]]},"reference":[{"key":"5736_CR1","doi-asserted-by":"crossref","unstructured":"Matsushime, H., Wang, L. H., Shibuya, M. Human c-ros-1 Gene Homologous to the v-ros Sequence of UR2 Sarcoma Virus Encodes for a Transmembrane Receptorlike Molecule. 6, 3000\u20133004 (1986).","DOI":"10.1128\/MCB.6.8.3000"},{"key":"5736_CR2","doi-asserted-by":"publisher","first-page":"4449","DOI":"10.1158\/1078-0432.CCR-11-3351","volume":"18","author":"VM Rimkunas","year":"2012","unstructured":"Rimkunas, V. M. et al. Analysis of receptor tyrosine kinase ROS1-positive tumors in non-small cell lung cancer: Identification of a FIG-ROS1 fusion. Clin. Cancer Res. \n                           18, 4449\u20134457 (2012).","journal-title":"Clin. Cancer Res."},{"key":"5736_CR3","doi-asserted-by":"publisher","first-page":"e15640","DOI":"10.1371\/journal.pone.0015640","volume":"6","author":"T-L Gu","year":"2011","unstructured":"Gu, T.-L. et al. Survey of tyrosine kinase signaling reveals ROS kinase fusions in human cholangiocarcinoma. PLoS One \n                           6, e15640 (2011).","journal-title":"PLoS One"},{"key":"5736_CR4","doi-asserted-by":"publisher","first-page":"4570","DOI":"10.1158\/1078-0432.CCR-12-0550","volume":"18","author":"KD Davies","year":"2012","unstructured":"Davies, K. D. et al. Identifying and targeting ROS1 gene fusions in non-small cell lung cancer. Clin. Cancer Res. \n                           18, 4570\u20134579 (2012).","journal-title":"Clin. Cancer Res."},{"key":"5736_CR5","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1038\/nm.2658","volume":"18","author":"K Takeuchi","year":"2012","unstructured":"Takeuchi, K. et al. RET, ROS1 and ALK fusions in lung cancer. Nat. Med \n                           18, 378\u201381 (2012).","journal-title":"Nat. Med"},{"key":"5736_CR6","doi-asserted-by":"publisher","first-page":"535","DOI":"10.1038\/nrc3775","volume":"14","author":"Z Chen","year":"2014","unstructured":"Chen, Z., Fillmore, C. M., Hammerman, P. S., Kim, C. F. & Wong, K.-K. Non-small-cell lung cancers: a heterogeneous set of diseases. Nat. Rev. Cancer \n                           14, 535\u2013546 (2014).","journal-title":"Nat. Rev. Cancer"},{"key":"5736_CR7","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1126\/science.1075762","volume":"298","author":"G Manning","year":"2002","unstructured":"Manning, G. The Protein Kinase Complement of the Human Genome. Science \n                           298, 1912\u20131934 (2002).","journal-title":"Science"},{"key":"5736_CR8","doi-asserted-by":"publisher","first-page":"992","DOI":"10.1200\/JCO.2014.58.3302","volume":"33","author":"J Mazi\u00e8res","year":"2015","unstructured":"Mazi\u00e8res, J. et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: Results from the EUROS1 cohort. J. Clin. Oncol. \n                           33, 992\u2013999 (2015).","journal-title":"J. Clin. 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PF-06463922 is a potent and selective next-generation ROS1\/ALK inhibitor capable of blocking crizotinib-resistant ROS1 mutations. Proc Natl Acad Sci USA \n                           112, 3493\u20133498 (2015).","journal-title":"Proc Natl Acad Sci USA"},{"key":"5736_CR12","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1158\/2159-8290.CD-16-1237","volume":"7","author":"SS Alexander Drilon","year":"2017","unstructured":"Alexander Drilon, S. S. et al. Safety and Antitumor Activity of the Multi-Targeted Pan-TRK, ROS1, and ALK Inhibitor Entrectinib (RXDX-101): Combined Results from Two Phase 1 Trials (ALKA-372-001 and STARTRK-1). Cancer Discov. \n                           7, 400\u2013409 (2017).","journal-title":"Cancer Discov."},{"key":"5736_CR13","doi-asserted-by":"publisher","first-page":"5983","DOI":"10.1158\/1078-0432.CCR-16-0917","volume":"22","author":"F Facchinetti","year":"2016","unstructured":"Facchinetti, F. et al. Crizotinib-resistant ROS1 mutations reveal a predictive kinase inhibitor sensitivity model for ROS1- and ALK-rearranged lung cancers. Clin. Cancer Res. \n                           22, 5983\u20135991 (2016).","journal-title":"Clin. Cancer Res."},{"key":"5736_CR14","doi-asserted-by":"publisher","first-page":"2395","DOI":"10.1056\/NEJMoa1215530","volume":"368","author":"MM Awad","year":"2013","unstructured":"Awad, M. M. et al. Acquired Resistance to Crizotinib from a Mutation in. CD74 \u2013 ROS1. N. Engl. J. Med. \n                           368, 2395\u20132401 (2013).","journal-title":"CD74 \u2013 ROS1. N. Engl. J. Med."},{"key":"5736_CR15","doi-asserted-by":"publisher","first-page":"2351","DOI":"10.1158\/1078-0432.CCR-15-2013","volume":"22","author":"A Drilon","year":"2015","unstructured":"Drilon, A. et al. A novel crizotinib-resistant solvent-front mutation responsive to cabozantinib therapy in a patient with ROS1-rearranged lung cancer. Clin. 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