{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T22:37:53Z","timestamp":1784932673178,"version":"3.55.0"},"reference-count":59,"publisher":"SAGE Publications","issue":"10","license":[{"start":{"date-parts":[[2023,10,1]],"date-time":"2023-10-01T00:00:00Z","timestamp":1696118400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"published-print":{"date-parts":[[2023,10]]},"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>\n                      Anaplastic thyroid cancer (ATC) is uniformly lethal.\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      mutation is present in 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      -mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      ATC cells, of highly active compounds in combination with BRAF inhibition showed multitargeting tyrosine kinase inhibitors (MTKIs) had the highest synergistic\/additive activity. Thus, we hypothesized that the combination of\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      inhibition and an MTKI is more effective than a single drug or combined BRAF and MEK inhibition in\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      -mutant ATC. We evaluated the effect of\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      inhibitors in combination with the MTKI axitinib and its mechanism(s) of action.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>\n                      We evaluated the effects of\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      inhibitors and axitinib alone and in combination in\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      models of\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      -mutant and wild-type ATC.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>\n                      The combination of axitinib and\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      inhibitors (dabrafenib and PLX4720) showed an additive effect on inhibiting cell proliferation based on the Chou\u2013Talalay algorithm in\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      -mutant ATC cell lines. This combination also significantly inhibited cell invasion and migration (\n                      <jats:italic toggle=\"yes\">p<\/jats:italic>\n                      \u2009&lt;\u20090.001) compared with the control. Dabrafenib and PLX4720 arrested ATC cells in the G0\/G1 phase. Axitinib arrested ATC cells in the G2\/M phase by decreasing phosphorylation of aurora kinase B (Thr232) and histone H3 (Ser10) proteins and by upregulating the c-JUN signaling pathway. The combination of BRAF inhibition and axitinib significantly inhibited tumor growth and was associated with improved survival in an orthotopic ATC model.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>\n                      The novel combination of axitinib and\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      inhibition enhanced anticancer activity in\n                      <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                      and\n                      <jats:italic toggle=\"yes\">in vivo<\/jats:italic>\n                      models of\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      -mutant ATC. This combination may have clinical utility in\n                      <jats:italic toggle=\"yes\">\n                        BRAF\n                        <jats:sup>V600E<\/jats:sup>\n                      <\/jats:italic>\n                      -mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1089\/thy.2023.0201","type":"journal-article","created":{"date-parts":[[2023,9,7]],"date-time":"2023-09-07T07:41:10Z","timestamp":1694072470000},"page":"1201-1214","update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":16,"title":["Combination\n                    <i>\n                      BRAF\n                      <sup>V600E<\/sup>\n                    <\/i>\n                    Inhibition with the Multitargeting Tyrosine Kinase Inhibitor Axitinib Shows Additive Anticancer Activity in\n                    <i>\n                      BRAF\n                      <sup>V600E<\/sup>\n                    <\/i>\n                    -Mutant Anaplastic Thyroid Cancer"],"prefix":"10.1177","volume":"33","author":[{"given":"Viswanath","family":"Gunda","sequence":"first","affiliation":[{"name":"Department of Surgery, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2336-8487","authenticated-orcid":false,"given":"Chandrayee","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangnan","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University, Stanford, California, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Zhang","sequence":"additional","affiliation":[{"name":"Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ya qin","family":"Zhang","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min","family":"Shen","sequence":"additional","affiliation":[{"name":"National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-1456","authenticated-orcid":false,"given":"Electron","family":"Kebebew","sequence":"additional","affiliation":[{"name":"Department of Surgery, Stanford University, Stanford, California, USA."},{"name":"Stanford Cancer Institute, Stanford University, Stanford, California, 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