{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T19:34:38Z","timestamp":1791228878093,"version":"4.1.0"},"reference-count":0,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T00:00:00Z","timestamp":1709078400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>ROS1 fusion-positive (ROS1+) nonsmall cell lung cancer (NSCLC) patients are highly sensitive to tyrosine kinase inhibitor (TKI) treatments. However, acquired TKI resistance remains the major hurdle preventing patients from experiencing prolonged benefits.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>107 advanced or metastatic ROS1+ NSCLC patients who progressed on crizotinib and lorlatinib were recruited. Tissue and plasma samples were collected at baseline (N = 50), postcrizotinib (N = 91), and postlorlatinib (N = 21), which were all subject to the 139-gene targeted next-generation DNA sequencing. Molecular dynamics modeling was performed to investigate the effects of ROS1 mutations on binding to different TKIs.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>In patients with postcrizotinib and postlorlatinib samples, an accumulation of on- and off-target resistance alterations after multiple TKI treatments was observed. ROS1 G2032R and MET amplification were the most common on-target and off-target alterations, respectively. Patients with CD74-ROS1 and SLC34A2-ROS1 had longer progression-free survival (PFS) (P &amp;lt; 0.001) and higher rates of resistance mutations (on-target, P = 0.001; off-target, P = 0.077) than other ROS1 fusion variants following crizotinib treatment. Ten distinct on-target resistance mutations were detected after TKI therapies, of which 4 were previously unreported (ROS1 L2010M, G1957A, D1988N, L1982V). Molecular dynamics simulations showed that all 4 mutations were refractory to crizotinib, while G1957A, D1988N, and L1982V were potentially sensitive to lorlatinib and entrectinib.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>This study provided a comprehensive portrait of TKI-resistance mechanisms in ROS1+ NSCLC patients. Using in silico simulations of TKI activity, novel secondary mutations that may confer TKI resistance were identified and may support clinical therapeutic decision-making.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/clinchem\/hvae008","type":"journal-article","created":{"date-parts":[[2024,2,28]],"date-time":"2024-02-28T18:18:56Z","timestamp":1709144336000},"page":"629-641","source":"Crossref","is-referenced-by-count":18,"title":["Mechanisms of Resistance to Tyrosine Kinase Inhibitors in <i>ROS1<\/i> Fusion-Positive Nonsmall Cell Lung Cancer"],"prefix":"10.1093","volume":"70","author":[{"given":"Xinmin","family":"Zhao","sequence":"first","affiliation":[{"name":"Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032 , China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China"},{"name":"Institute of Thoracic Oncology, Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xin","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032 , China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China"},{"name":"Institute of Thoracic Oncology, Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6205-3122","authenticated-orcid":false,"given":"Hanlin","family":"Chen","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute, Nanjing Geneseeq Technology Inc. , Nanjing 211166 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hairong","family":"Bao","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute, Nanjing Geneseeq Technology Inc. , Nanjing 211166 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianghua","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032 , China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China"},{"name":"Institute of Thoracic Oncology, Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032 , China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China"},{"name":"Institute of Thoracic Oncology, Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hua","family":"Bao","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute, Nanjing Geneseeq Technology Inc. , Nanjing 211166 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaohui","family":"Pang","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute, Nanjing Geneseeq Technology Inc. , Nanjing 211166 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sha","family":"Wang","sequence":"additional","affiliation":[{"name":"Geneseeq Research Institute, Nanjing Geneseeq Technology Inc. , Nanjing 211166 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialei","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Thoracic Medical Oncology, Fudan University Shanghai Cancer Center , Shanghai 200032 , China"},{"name":"Department of Oncology, Shanghai Medical College, Fudan University , Shanghai 200032 , China"},{"name":"Institute of Thoracic Oncology, Fudan University , Shanghai 200032 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,2,28]]},"container-title":["Clinical 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