p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer
Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene...
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| creator | McFadden, David G Vernon, Amanda Santiago, Philip M Martinez-McFaline, Raul Bhutkar, Arjun Crowley, Denise M McMahon, Martin Sadow, Peter M Jacks, Tyler |
| description | Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF -mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf ⱽ⁶⁰⁰ᴱ mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma. |
| doi_str_mv | 10.1073/pnas.1404357111 |
| format | Article |
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The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF -mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf ⱽ⁶⁰⁰ᴱ mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.</description><identifier>ISSN: 0027-8424</identifier><identifier>EISSN: 1091-6490</identifier><identifier>DOI: 10.1073/pnas.1404357111</identifier><identifier>PMID: 24711431</identifier><language>eng</language><publisher>United States: National Academy of Sciences</publisher><subject>animal models ; Animals ; Biological Sciences ; carcinoma ; Carcinoma - blood ; Carcinoma - drug therapy ; Carcinoma - genetics ; Carcinoma - pathology ; Carcinoma, Papillary ; Cell Differentiation - drug effects ; Cell Differentiation - genetics ; Cell Proliferation - drug effects ; clinical trials ; disease incidence ; Disease Models, Animal ; Disease Progression ; gene expression ; Gene Expression Regulation, Neoplastic - drug effects ; Homozygote ; Humans ; immunohistochemistry ; Kinases ; MAP Kinase Signaling System - drug effects ; MAP Kinase Signaling System - genetics ; metastasis ; Mice ; Mice, Transgenic ; mitogen-activated protein kinase ; Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors ; Mutation ; Mutation - genetics ; Neoplasm Grading ; oncogenes ; Oncology ; PNAS Plus ; Protein Kinase Inhibitors - therapeutic use ; Proto-Oncogene Proteins B-raf - antagonists & inhibitors ; Proto-Oncogene Proteins B-raf - genetics ; remission ; Rodents ; sarcoma ; Signal transduction ; Survival analysis ; Thyroid cancer ; Thyroid Cancer, Papillary ; Thyroid Carcinoma, Anaplastic ; Thyroid Gland - drug effects ; Thyroid Gland - pathology ; thyroid neoplasms ; Thyroid Neoplasms - blood ; Thyroid Neoplasms - drug therapy ; Thyroid Neoplasms - genetics ; Thyroid Neoplasms - pathology ; Thyrotropin - blood ; transgenic animals ; Tumor Suppressor Protein p53 - metabolism ; ultrasonography</subject><ispartof>Proceedings of the National Academy of Sciences - PNAS, 2014-04, Vol.111 (16), p.E1600-E1609</ispartof><rights>Copyright National Academy of Sciences Apr 22, 2014</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c503t-d3a5a6777c115b36bdbeb50e148e6e5355026b1d78a05dfe66d9200b800a27143</citedby><cites>FETCH-LOGICAL-c503t-d3a5a6777c115b36bdbeb50e148e6e5355026b1d78a05dfe66d9200b800a27143</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Uhttp://www.pnas.org/content/111/16.cover.gif</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000830/pdf/$$EPDF$$P50$$Gpubmedcentral$$H</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4000830/$$EHTML$$P50$$Gpubmedcentral$$H</linktohtml><link.rule.ids>230,314,723,776,780,881,27901,27902,53766,53768</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24711431$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>McFadden, David G</creatorcontrib><creatorcontrib>Vernon, Amanda</creatorcontrib><creatorcontrib>Santiago, Philip M</creatorcontrib><creatorcontrib>Martinez-McFaline, Raul</creatorcontrib><creatorcontrib>Bhutkar, Arjun</creatorcontrib><creatorcontrib>Crowley, Denise M</creatorcontrib><creatorcontrib>McMahon, Martin</creatorcontrib><creatorcontrib>Sadow, Peter M</creatorcontrib><creatorcontrib>Jacks, Tyler</creatorcontrib><title>p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer</title><title>Proceedings of the National Academy of Sciences - PNAS</title><addtitle>Proc Natl Acad Sci U S A</addtitle><description>Anaplastic thyroid carcinoma (ATC) has among the worst prognoses of any solid malignancy. The low incidence of the disease has in part precluded systematic clinical trials and tissue collection, and there has been little progress in developing effective therapies. v-raf murine sarcoma viral oncogene homolog B (BRAF) and tumor protein p53 (TP53) mutations cooccur in a high proportion of ATCs, particularly those associated with a precursor papillary thyroid carcinoma (PTC). To develop an adult-onset model of BRAF -mutant ATC, we generated a thyroid-specific CreER transgenic mouse. We used a Cre-regulated Braf ⱽ⁶⁰⁰ᴱ mouse and a conditional Trp53 allelic series to demonstrate that p53 constrains progression from PTC to ATC. Gene expression and immunohistochemical analyses of murine tumors identified the cardinal features of human ATC including loss of differentiation, local invasion, distant metastasis, and rapid lethality. We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.</description><subject>animal models</subject><subject>Animals</subject><subject>Biological Sciences</subject><subject>carcinoma</subject><subject>Carcinoma - blood</subject><subject>Carcinoma - drug therapy</subject><subject>Carcinoma - genetics</subject><subject>Carcinoma - pathology</subject><subject>Carcinoma, Papillary</subject><subject>Cell Differentiation - drug effects</subject><subject>Cell Differentiation - genetics</subject><subject>Cell Proliferation - drug effects</subject><subject>clinical trials</subject><subject>disease incidence</subject><subject>Disease Models, Animal</subject><subject>Disease Progression</subject><subject>gene expression</subject><subject>Gene Expression Regulation, Neoplastic - drug effects</subject><subject>Homozygote</subject><subject>Humans</subject><subject>immunohistochemistry</subject><subject>Kinases</subject><subject>MAP Kinase Signaling System - drug effects</subject><subject>MAP Kinase Signaling System - genetics</subject><subject>metastasis</subject><subject>Mice</subject><subject>Mice, Transgenic</subject><subject>mitogen-activated protein kinase</subject><subject>Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors</subject><subject>Mutation</subject><subject>Mutation - genetics</subject><subject>Neoplasm Grading</subject><subject>oncogenes</subject><subject>Oncology</subject><subject>PNAS Plus</subject><subject>Protein Kinase Inhibitors - therapeutic use</subject><subject>Proto-Oncogene Proteins B-raf - antagonists & inhibitors</subject><subject>Proto-Oncogene Proteins B-raf - genetics</subject><subject>remission</subject><subject>Rodents</subject><subject>sarcoma</subject><subject>Signal transduction</subject><subject>Survival analysis</subject><subject>Thyroid cancer</subject><subject>Thyroid Cancer, Papillary</subject><subject>Thyroid Carcinoma, Anaplastic</subject><subject>Thyroid Gland - drug effects</subject><subject>Thyroid Gland - pathology</subject><subject>thyroid neoplasms</subject><subject>Thyroid Neoplasms - blood</subject><subject>Thyroid Neoplasms - drug therapy</subject><subject>Thyroid Neoplasms - genetics</subject><subject>Thyroid Neoplasms - pathology</subject><subject>Thyrotropin - blood</subject><subject>transgenic animals</subject><subject>Tumor Suppressor Protein p53 - metabolism</subject><subject>ultrasonography</subject><issn>0027-8424</issn><issn>1091-6490</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpdkTtvFDEUhS0EIptATQeWaNJMcq-fsw0SROEhRaKA1JbH49k4mrEHexYp_x4vuyyBxi7ud4_P8SHkFcIFguaXc7TlAgUILjUiPiErhDU2SqzhKVkBMN20gokTclrKPQCsZQvPyQkTlRYcV6TMklOXYlmyDbHQOadN9qWEFOmSqI12Hm1ZgqPL3UNOoafOZhdimiwNkVr6IduhmbaLjQud0rb4evZ-pGmgs53DONr88Gg3Op9fkGeDHYt_ebjPyO3H6-9Xn5ubr5--XL2_aZwEvjQ9t9IqrbVDlB1XXd_5ToJH0XrlJZcSmOqw160F2Q9eqX7NALoWwDJd452Rd3vdedtNvnc-1pCjmXOYqimTbDD_TmK4M5v004j6Uy2HKnB-EMjpx9aXxUyhOF8zRV-jGmyBI0glWEXf_ofep22ONZ5ByRCZrtYqdbmnXE6lZD8czSCYXaFmV6j5W2jdeP04w5H_02AF6AHYbR7lEA0qc43q96tv9shgk7GbHIq5_cZgN0MhWs34L09psSI</recordid><startdate>20140422</startdate><enddate>20140422</enddate><creator>McFadden, David G</creator><creator>Vernon, Amanda</creator><creator>Santiago, Philip M</creator><creator>Martinez-McFaline, Raul</creator><creator>Bhutkar, Arjun</creator><creator>Crowley, Denise M</creator><creator>McMahon, Martin</creator><creator>Sadow, Peter M</creator><creator>Jacks, Tyler</creator><general>National Academy of Sciences</general><general>National Acad Sciences</general><scope>FBQ</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QG</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7SN</scope><scope>7SS</scope><scope>7T5</scope><scope>7TK</scope><scope>7TM</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>M7N</scope><scope>P64</scope><scope>RC3</scope><scope>7S9</scope><scope>L.6</scope><scope>5PM</scope></search><sort><creationdate>20140422</creationdate><title>p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer</title><author>McFadden, David G ; Vernon, Amanda ; Santiago, Philip M ; Martinez-McFaline, Raul ; Bhutkar, Arjun ; Crowley, Denise M ; McMahon, Martin ; Sadow, Peter M ; Jacks, Tyler</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c503t-d3a5a6777c115b36bdbeb50e148e6e5355026b1d78a05dfe66d9200b800a27143</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>animal models</topic><topic>Animals</topic><topic>Biological Sciences</topic><topic>carcinoma</topic><topic>Carcinoma - 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We used small-animal ultrasound imaging to monitor autochthonous tumors and showed that treatment with the selective BRAF inhibitor PLX4720 improved survival but did not lead to tumor regression or suppress signaling through the MAPK pathway. The combination of PLX4720 and the mapk/Erk kinase (MEK) inhibitor PD0325901 more completely suppressed MAPK pathway activation in mouse and human ATC cell lines and improved the structural response and survival of ATC-bearing animals. This model expands the limited repertoire of autochthonous models of clinically aggressive thyroid cancer, and these data suggest that small-molecule MAPK pathway inhibitors hold clinical promise in the treatment of advanced thyroid carcinoma.</abstract><cop>United States</cop><pub>National Academy of Sciences</pub><pmid>24711431</pmid><doi>10.1073/pnas.1404357111</doi><oa>free_for_read</oa></addata></record> |
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| subjects | animal models Animals Biological Sciences carcinoma Carcinoma - blood Carcinoma - drug therapy Carcinoma - genetics Carcinoma - pathology Carcinoma, Papillary Cell Differentiation - drug effects Cell Differentiation - genetics Cell Proliferation - drug effects clinical trials disease incidence Disease Models, Animal Disease Progression gene expression Gene Expression Regulation, Neoplastic - drug effects Homozygote Humans immunohistochemistry Kinases MAP Kinase Signaling System - drug effects MAP Kinase Signaling System - genetics metastasis Mice Mice, Transgenic mitogen-activated protein kinase Mitogen-Activated Protein Kinase Kinases - antagonists & inhibitors Mutation Mutation - genetics Neoplasm Grading oncogenes Oncology PNAS Plus Protein Kinase Inhibitors - therapeutic use Proto-Oncogene Proteins B-raf - antagonists & inhibitors Proto-Oncogene Proteins B-raf - genetics remission Rodents sarcoma Signal transduction Survival analysis Thyroid cancer Thyroid Cancer, Papillary Thyroid Carcinoma, Anaplastic Thyroid Gland - drug effects Thyroid Gland - pathology thyroid neoplasms Thyroid Neoplasms - blood Thyroid Neoplasms - drug therapy Thyroid Neoplasms - genetics Thyroid Neoplasms - pathology Thyrotropin - blood transgenic animals Tumor Suppressor Protein p53 - metabolism ultrasonography |
| title | p53 constrains progression to anaplastic thyroid carcinoma in a Braf-mutant mouse model of papillary thyroid cancer |
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