Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer
Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance. HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion w...
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| Veröffentlicht in: | Clinical cancer research 2017-11, Vol.23 (22), p.7006-7019 |
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| creator | Sabbaghi, MohammadA Gil-Gómez, Gabriel Guardia, Cristina Servitja, Sonia Arpí, Oriol García-Alonso, Sara Menendez, Silvia Arumi-Uria, Montserrat Serrano, Laia Salido, Marta Muntasell, Aura Martínez-García, Maria Zazo, Sandra Chamizo, Cristina González-Alonso, Paula Madoz-Gúrpide, Juan Eroles, Pilar Arribas, Joaquin Tusquets, Ignasi Lluch, Ana Pandiella, Atanasio Rojo, Federico Rovira, Ana Albanell, Joan |
| description | Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.
HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate
were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human
-positive breast cancer explants.
We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells.
knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing
partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.
Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer.
. |
| doi_str_mv | 10.1158/1078-0432.CCR-17-0696 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_csuc_</sourceid><recordid>TN_cdi_csuc_recercat_oai_recercat_cat_2072_315057</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>1983419700</sourcerecordid><originalsourceid>FETCH-LOGICAL-c544t-36f6abf448d265b8a3659e55c39a733a7beca7c171db21ae9d036e270abb4d9a3</originalsourceid><addsrcrecordid>eNpdkU9v1DAQxS0EoqXwEUCRuJSDi8d_YufYpoVWKkJaLWfLcSaSq02ya8dI5dPj0C1IHCx7PL_37NEj5D2wCwBlPgPThjIp-EXbbihoyuqmfkFOQSlNBa_Vy3J-Zk7Im5QeGAMJTL4mJ9wYXkBzSg7XOKBfwk-s2ke_C1N1BdXd1OdyN09VqbfRpSX_yqPrKI6Lm1KYsDrf0utv8Km69IccIvbVBlNIpetxFd3ebDjdzyn8cb6KWDyqdu3Gt-TV4HYJ3x33M_Ljy822vaX337_etZf31CspFyrqoXbdIKXpyzCdcaJWDSrlReO0EE536J32oKHvODhseiZq5Jq5rpN948QZgSdfn7K3EcvT3i12duFfsS7ONLcCFFO6aM6fNPs4HzKmxY4hedzt3IRzThYawaQBzZuCfvwPfZhznMpEhTJCQqMZK5Q6fiLOKUUc7D6G0cVHC8yuOdo1I7tmZEuOFrRdcyy6D0f33I3Y_1U9Byd-Aydnl2c</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1983419700</pqid></control><display><type>article</type><title>Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer</title><source>MEDLINE</source><source>American Association for Cancer Research</source><source>Recercat</source><source>Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals</source><source>Alma/SFX Local Collection</source><creator>Sabbaghi, MohammadA ; Gil-Gómez, Gabriel ; Guardia, Cristina ; Servitja, Sonia ; Arpí, Oriol ; García-Alonso, Sara ; Menendez, Silvia ; Arumi-Uria, Montserrat ; Serrano, Laia ; Salido, Marta ; Muntasell, Aura ; Martínez-García, Maria ; Zazo, Sandra ; Chamizo, Cristina ; González-Alonso, Paula ; Madoz-Gúrpide, Juan ; Eroles, Pilar ; Arribas, Joaquin ; Tusquets, Ignasi ; Lluch, Ana ; Pandiella, Atanasio ; Rojo, Federico ; Rovira, Ana ; Albanell, Joan</creator><creatorcontrib>Sabbaghi, MohammadA ; Gil-Gómez, Gabriel ; Guardia, Cristina ; Servitja, Sonia ; Arpí, Oriol ; García-Alonso, Sara ; Menendez, Silvia ; Arumi-Uria, Montserrat ; Serrano, Laia ; Salido, Marta ; Muntasell, Aura ; Martínez-García, Maria ; Zazo, Sandra ; Chamizo, Cristina ; González-Alonso, Paula ; Madoz-Gúrpide, Juan ; Eroles, Pilar ; Arribas, Joaquin ; Tusquets, Ignasi ; Lluch, Ana ; Pandiella, Atanasio ; Rojo, Federico ; Rovira, Ana ; Albanell, Joan</creatorcontrib><description>Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.
HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate
were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human
-positive breast cancer explants.
We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells.
knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing
partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.
Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer.
.</description><identifier>ISSN: 1078-0432</identifier><identifier>EISSN: 1557-3265</identifier><identifier>DOI: 10.1158/1078-0432.CCR-17-0696</identifier><identifier>PMID: 28821558</identifier><language>eng</language><publisher>United States: American Association for Cancer Research Inc</publisher><subject>Accumulation ; Animals ; Apoptosis ; Apoptosis - drug effects ; Apoptosis - genetics ; Auditory defects ; Breast cancer ; Breast Neoplasms - drug therapy ; Breast Neoplasms - genetics ; Breast Neoplasms - metabolism ; Breast Neoplasms - pathology ; Cancer ; CDC2 Protein Kinase - genetics ; CDC2 Protein Kinase - metabolism ; Cell Line, Tumor ; Cyclin B1 ; Cyclin B1 - deficiency ; Cyclin B1 - metabolism ; Càncer ; Disease Models, Animal ; Drug Resistance, Neoplasm - genetics ; ErbB-2 protein ; Experimental design ; Explants ; Female ; G2 Phase Cell Cycle Checkpoints - drug effects ; G2 Phase Cell Cycle Checkpoints - genetics ; Humans ; Immunotherapy ; Kinases ; Mama ; Maytansine - analogs & derivatives ; Maytansine - pharmacology ; Mice ; Monoclonal antibodies ; Pharmacodynamics ; Pharmacology ; Protein Binding ; Receptor, ErbB-2 - genetics ; Receptor, ErbB-2 - metabolism ; siRNA ; Targeted cancer therapy ; Tractament ; Trastuzumab ; Trastuzumab - pharmacology ; Xenograft Model Antitumor Assays</subject><ispartof>Clinical cancer research, 2017-11, Vol.23 (22), p.7006-7019</ispartof><rights>2017 American Association for Cancer Research.</rights><rights>Copyright American Association for Cancer Research Inc Nov 15, 2017</rights><rights>info:eu-repo/semantics/embargoedAccess © American Association for Cancer Research (AACR) <a href="http://dx.doi.org/10.1158/1078-0432.CCR-17-0696">http://dx.doi.org/10.1158/1078-0432.CCR-17-0696</a></rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c544t-36f6abf448d265b8a3659e55c39a733a7beca7c171db21ae9d036e270abb4d9a3</citedby><cites>FETCH-LOGICAL-c544t-36f6abf448d265b8a3659e55c39a733a7beca7c171db21ae9d036e270abb4d9a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,3343,26951,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28821558$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sabbaghi, MohammadA</creatorcontrib><creatorcontrib>Gil-Gómez, Gabriel</creatorcontrib><creatorcontrib>Guardia, Cristina</creatorcontrib><creatorcontrib>Servitja, Sonia</creatorcontrib><creatorcontrib>Arpí, Oriol</creatorcontrib><creatorcontrib>García-Alonso, Sara</creatorcontrib><creatorcontrib>Menendez, Silvia</creatorcontrib><creatorcontrib>Arumi-Uria, Montserrat</creatorcontrib><creatorcontrib>Serrano, Laia</creatorcontrib><creatorcontrib>Salido, Marta</creatorcontrib><creatorcontrib>Muntasell, Aura</creatorcontrib><creatorcontrib>Martínez-García, Maria</creatorcontrib><creatorcontrib>Zazo, Sandra</creatorcontrib><creatorcontrib>Chamizo, Cristina</creatorcontrib><creatorcontrib>González-Alonso, Paula</creatorcontrib><creatorcontrib>Madoz-Gúrpide, Juan</creatorcontrib><creatorcontrib>Eroles, Pilar</creatorcontrib><creatorcontrib>Arribas, Joaquin</creatorcontrib><creatorcontrib>Tusquets, Ignasi</creatorcontrib><creatorcontrib>Lluch, Ana</creatorcontrib><creatorcontrib>Pandiella, Atanasio</creatorcontrib><creatorcontrib>Rojo, Federico</creatorcontrib><creatorcontrib>Rovira, Ana</creatorcontrib><creatorcontrib>Albanell, Joan</creatorcontrib><title>Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer</title><title>Clinical cancer research</title><addtitle>Clin Cancer Res</addtitle><description>Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.
HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate
were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human
-positive breast cancer explants.
We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells.
knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing
partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.
Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer.
.</description><subject>Accumulation</subject><subject>Animals</subject><subject>Apoptosis</subject><subject>Apoptosis - drug effects</subject><subject>Apoptosis - genetics</subject><subject>Auditory defects</subject><subject>Breast cancer</subject><subject>Breast Neoplasms - drug therapy</subject><subject>Breast Neoplasms - genetics</subject><subject>Breast Neoplasms - metabolism</subject><subject>Breast Neoplasms - pathology</subject><subject>Cancer</subject><subject>CDC2 Protein Kinase - genetics</subject><subject>CDC2 Protein Kinase - metabolism</subject><subject>Cell Line, Tumor</subject><subject>Cyclin B1</subject><subject>Cyclin B1 - deficiency</subject><subject>Cyclin B1 - metabolism</subject><subject>Càncer</subject><subject>Disease Models, Animal</subject><subject>Drug Resistance, Neoplasm - genetics</subject><subject>ErbB-2 protein</subject><subject>Experimental design</subject><subject>Explants</subject><subject>Female</subject><subject>G2 Phase Cell Cycle Checkpoints - drug effects</subject><subject>G2 Phase Cell Cycle Checkpoints - genetics</subject><subject>Humans</subject><subject>Immunotherapy</subject><subject>Kinases</subject><subject>Mama</subject><subject>Maytansine - analogs & derivatives</subject><subject>Maytansine - pharmacology</subject><subject>Mice</subject><subject>Monoclonal antibodies</subject><subject>Pharmacodynamics</subject><subject>Pharmacology</subject><subject>Protein Binding</subject><subject>Receptor, ErbB-2 - genetics</subject><subject>Receptor, ErbB-2 - metabolism</subject><subject>siRNA</subject><subject>Targeted cancer therapy</subject><subject>Tractament</subject><subject>Trastuzumab</subject><subject>Trastuzumab - pharmacology</subject><subject>Xenograft Model Antitumor Assays</subject><issn>1078-0432</issn><issn>1557-3265</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>XX2</sourceid><recordid>eNpdkU9v1DAQxS0EoqXwEUCRuJSDi8d_YufYpoVWKkJaLWfLcSaSq02ya8dI5dPj0C1IHCx7PL_37NEj5D2wCwBlPgPThjIp-EXbbihoyuqmfkFOQSlNBa_Vy3J-Zk7Im5QeGAMJTL4mJ9wYXkBzSg7XOKBfwk-s2ke_C1N1BdXd1OdyN09VqbfRpSX_yqPrKI6Lm1KYsDrf0utv8Km69IccIvbVBlNIpetxFd3ebDjdzyn8cb6KWDyqdu3Gt-TV4HYJ3x33M_Ljy822vaX337_etZf31CspFyrqoXbdIKXpyzCdcaJWDSrlReO0EE536J32oKHvODhseiZq5Jq5rpN948QZgSdfn7K3EcvT3i12duFfsS7ONLcCFFO6aM6fNPs4HzKmxY4hedzt3IRzThYawaQBzZuCfvwPfZhznMpEhTJCQqMZK5Q6fiLOKUUc7D6G0cVHC8yuOdo1I7tmZEuOFrRdcyy6D0f33I3Y_1U9Byd-Aydnl2c</recordid><startdate>20171115</startdate><enddate>20171115</enddate><creator>Sabbaghi, MohammadA</creator><creator>Gil-Gómez, Gabriel</creator><creator>Guardia, Cristina</creator><creator>Servitja, Sonia</creator><creator>Arpí, Oriol</creator><creator>García-Alonso, Sara</creator><creator>Menendez, Silvia</creator><creator>Arumi-Uria, Montserrat</creator><creator>Serrano, Laia</creator><creator>Salido, Marta</creator><creator>Muntasell, Aura</creator><creator>Martínez-García, Maria</creator><creator>Zazo, Sandra</creator><creator>Chamizo, Cristina</creator><creator>González-Alonso, Paula</creator><creator>Madoz-Gúrpide, Juan</creator><creator>Eroles, Pilar</creator><creator>Arribas, Joaquin</creator><creator>Tusquets, Ignasi</creator><creator>Lluch, Ana</creator><creator>Pandiella, Atanasio</creator><creator>Rojo, Federico</creator><creator>Rovira, Ana</creator><creator>Albanell, Joan</creator><general>American Association for Cancer Research Inc</general><general>American Association for Cancer Research (AACR)</general><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>7QO</scope><scope>7T5</scope><scope>7TO</scope><scope>7U9</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>7X8</scope><scope>XX2</scope></search><sort><creationdate>20171115</creationdate><title>Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer</title><author>Sabbaghi, MohammadA ; Gil-Gómez, Gabriel ; Guardia, Cristina ; Servitja, Sonia ; Arpí, Oriol ; García-Alonso, Sara ; Menendez, Silvia ; Arumi-Uria, Montserrat ; Serrano, Laia ; Salido, Marta ; Muntasell, Aura ; Martínez-García, Maria ; Zazo, Sandra ; Chamizo, Cristina ; González-Alonso, Paula ; Madoz-Gúrpide, Juan ; Eroles, Pilar ; Arribas, Joaquin ; Tusquets, Ignasi ; Lluch, Ana ; Pandiella, Atanasio ; Rojo, Federico ; Rovira, Ana ; Albanell, Joan</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c544t-36f6abf448d265b8a3659e55c39a733a7beca7c171db21ae9d036e270abb4d9a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Accumulation</topic><topic>Animals</topic><topic>Apoptosis</topic><topic>Apoptosis - drug effects</topic><topic>Apoptosis - genetics</topic><topic>Auditory defects</topic><topic>Breast cancer</topic><topic>Breast Neoplasms - drug therapy</topic><topic>Breast Neoplasms - genetics</topic><topic>Breast Neoplasms - metabolism</topic><topic>Breast Neoplasms - pathology</topic><topic>Cancer</topic><topic>CDC2 Protein Kinase - genetics</topic><topic>CDC2 Protein Kinase - metabolism</topic><topic>Cell Line, Tumor</topic><topic>Cyclin B1</topic><topic>Cyclin B1 - deficiency</topic><topic>Cyclin B1 - metabolism</topic><topic>Càncer</topic><topic>Disease Models, Animal</topic><topic>Drug Resistance, Neoplasm - genetics</topic><topic>ErbB-2 protein</topic><topic>Experimental design</topic><topic>Explants</topic><topic>Female</topic><topic>G2 Phase Cell Cycle Checkpoints - drug effects</topic><topic>G2 Phase Cell Cycle Checkpoints - genetics</topic><topic>Humans</topic><topic>Immunotherapy</topic><topic>Kinases</topic><topic>Mama</topic><topic>Maytansine - analogs & derivatives</topic><topic>Maytansine - pharmacology</topic><topic>Mice</topic><topic>Monoclonal antibodies</topic><topic>Pharmacodynamics</topic><topic>Pharmacology</topic><topic>Protein Binding</topic><topic>Receptor, ErbB-2 - genetics</topic><topic>Receptor, ErbB-2 - metabolism</topic><topic>siRNA</topic><topic>Targeted cancer therapy</topic><topic>Tractament</topic><topic>Trastuzumab</topic><topic>Trastuzumab - pharmacology</topic><topic>Xenograft Model Antitumor Assays</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sabbaghi, MohammadA</creatorcontrib><creatorcontrib>Gil-Gómez, Gabriel</creatorcontrib><creatorcontrib>Guardia, Cristina</creatorcontrib><creatorcontrib>Servitja, Sonia</creatorcontrib><creatorcontrib>Arpí, Oriol</creatorcontrib><creatorcontrib>García-Alonso, Sara</creatorcontrib><creatorcontrib>Menendez, Silvia</creatorcontrib><creatorcontrib>Arumi-Uria, Montserrat</creatorcontrib><creatorcontrib>Serrano, Laia</creatorcontrib><creatorcontrib>Salido, Marta</creatorcontrib><creatorcontrib>Muntasell, Aura</creatorcontrib><creatorcontrib>Martínez-García, Maria</creatorcontrib><creatorcontrib>Zazo, Sandra</creatorcontrib><creatorcontrib>Chamizo, Cristina</creatorcontrib><creatorcontrib>González-Alonso, Paula</creatorcontrib><creatorcontrib>Madoz-Gúrpide, Juan</creatorcontrib><creatorcontrib>Eroles, Pilar</creatorcontrib><creatorcontrib>Arribas, Joaquin</creatorcontrib><creatorcontrib>Tusquets, Ignasi</creatorcontrib><creatorcontrib>Lluch, Ana</creatorcontrib><creatorcontrib>Pandiella, Atanasio</creatorcontrib><creatorcontrib>Rojo, Federico</creatorcontrib><creatorcontrib>Rovira, Ana</creatorcontrib><creatorcontrib>Albanell, Joan</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Biotechnology Research Abstracts</collection><collection>Immunology Abstracts</collection><collection>Oncogenes and Growth Factors Abstracts</collection><collection>Virology and AIDS Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>MEDLINE - Academic</collection><collection>Recercat</collection><jtitle>Clinical cancer research</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sabbaghi, MohammadA</au><au>Gil-Gómez, Gabriel</au><au>Guardia, Cristina</au><au>Servitja, Sonia</au><au>Arpí, Oriol</au><au>García-Alonso, Sara</au><au>Menendez, Silvia</au><au>Arumi-Uria, Montserrat</au><au>Serrano, Laia</au><au>Salido, Marta</au><au>Muntasell, Aura</au><au>Martínez-García, Maria</au><au>Zazo, Sandra</au><au>Chamizo, Cristina</au><au>González-Alonso, Paula</au><au>Madoz-Gúrpide, Juan</au><au>Eroles, Pilar</au><au>Arribas, Joaquin</au><au>Tusquets, Ignasi</au><au>Lluch, Ana</au><au>Pandiella, Atanasio</au><au>Rojo, Federico</au><au>Rovira, Ana</au><au>Albanell, Joan</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer</atitle><jtitle>Clinical cancer research</jtitle><addtitle>Clin Cancer Res</addtitle><date>2017-11-15</date><risdate>2017</risdate><volume>23</volume><issue>22</issue><spage>7006</spage><epage>7019</epage><pages>7006-7019</pages><issn>1078-0432</issn><eissn>1557-3265</eissn><abstract>Trastuzumab-emtansine (T-DM1) is a standard treatment in advanced HER2-positive breast cancer. However, resistance inevitably occurs. We aimed to identify mechanisms of acquired T-DM1 resistance.
HER2-positive breast cancer cells (HCC1954, HCC1419, SKBR3, and BT474) were treated in a pulse-fashion with T-DM1 to induce a resistant phenotype. Cellular and molecular effects of T-DM1 in parental versus resistant cells were compared. CDK1 kinase activity and cyclin B1 expression were assayed under various conditions. Genetic modifications to up- or downregulate
were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human
-positive breast cancer explants.
We obtained three cell lines with different levels of acquired T-DM1 resistance (HCC1954/TDR, HCC1419/TDR, and SKBR3/TDR cells). HER2 remained amplified in the resistant cells. Binding to HER2 and intracellular uptake of T-DM1 were maintained in resistant cells. T-DM1 induced cyclin B1 accumulation in sensitive but not resistant cells.
knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing
partially sensitized resistant cells. In a series of 18 HER2-positive breast cancer fresh explants, T-DM1 effects on proliferation and apoptosis paralleled cyclin B1 accumulation.
Defective cyclin B1 induction by T-DM1 mediates acquired resistance in HER2-positive breast cancer cells. These results support the testing of cyclin B1 induction upon T-DM1 treatment as a pharmacodynamic predictor in HER2-positive breast cancer.
.</abstract><cop>United States</cop><pub>American Association for Cancer Research Inc</pub><pmid>28821558</pmid><doi>10.1158/1078-0432.CCR-17-0696</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1078-0432 |
| ispartof | Clinical cancer research, 2017-11, Vol.23 (22), p.7006-7019 |
| issn | 1078-0432 1557-3265 |
| language | eng |
| recordid | cdi_csuc_recercat_oai_recercat_cat_2072_315057 |
| source | MEDLINE; American Association for Cancer Research; Recercat; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals; Alma/SFX Local Collection |
| subjects | Accumulation Animals Apoptosis Apoptosis - drug effects Apoptosis - genetics Auditory defects Breast cancer Breast Neoplasms - drug therapy Breast Neoplasms - genetics Breast Neoplasms - metabolism Breast Neoplasms - pathology Cancer CDC2 Protein Kinase - genetics CDC2 Protein Kinase - metabolism Cell Line, Tumor Cyclin B1 Cyclin B1 - deficiency Cyclin B1 - metabolism Càncer Disease Models, Animal Drug Resistance, Neoplasm - genetics ErbB-2 protein Experimental design Explants Female G2 Phase Cell Cycle Checkpoints - drug effects G2 Phase Cell Cycle Checkpoints - genetics Humans Immunotherapy Kinases Mama Maytansine - analogs & derivatives Maytansine - pharmacology Mice Monoclonal antibodies Pharmacodynamics Pharmacology Protein Binding Receptor, ErbB-2 - genetics Receptor, ErbB-2 - metabolism siRNA Targeted cancer therapy Tractament Trastuzumab Trastuzumab - pharmacology Xenograft Model Antitumor Assays |
| title | Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-09T10%3A05%3A00IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_csuc_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Defective%20Cyclin%20B1%20Induction%20in%20Trastuzumab-emtansine%20(T-DM1)%20Acquired%20Resistance%20in%20HER2-positive%20Breast%20Cancer&rft.jtitle=Clinical%20cancer%20research&rft.au=Sabbaghi,%20MohammadA&rft.date=2017-11-15&rft.volume=23&rft.issue=22&rft.spage=7006&rft.epage=7019&rft.pages=7006-7019&rft.issn=1078-0432&rft.eissn=1557-3265&rft_id=info:doi/10.1158/1078-0432.CCR-17-0696&rft_dat=%3Cproquest_csuc_%3E1983419700%3C/proquest_csuc_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1983419700&rft_id=info:pmid/28821558&rfr_iscdi=true |