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Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer

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dc.contributor.author Sabbaghi Mehrjardi, Mohammad Ali
dc.contributor.author Gil Gómez, Gabriel
dc.contributor.author Guardia Laguarta, Cristina
dc.contributor.author Servitja Tormo, Sonia
dc.contributor.author Arpí Llucià, Oriol
dc.contributor.author Menendez Romero, Silvia
dc.contributor.author Arumí, Montserrat
dc.contributor.author Serrano, Laia
dc.contributor.author Salido Galeote, Marta
dc.contributor.author Muntasell i Castellví, Aura, 1972-
dc.contributor.author Martínez-García, Maria
dc.contributor.author Tusquets Trias de Bes, Ignacio
dc.contributor.author Rovira Guerín, Ana
dc.contributor.author Albanell Mestres, Joan
dc.date.accessioned 2018-05-07T07:52:48Z
dc.date.issued 2017
dc.identifier.citation Sabbaghi M, Gil-Gómez G, Guardia C, Servitja S, Arpí O, García-Alonso S. et al. Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer. Clin Cancer Res. 2017 Nov 15;23(22):7006-19. DOI: 10.1158/1078-0432.CCR-17-0696
dc.identifier.issn 1078-0432
dc.identifier.uri http://hdl.handle.net/10230/34570
dc.description.abstract Purpose: 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.Experimental Design: 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 cyclin B1 were conducted. Effects of T-DM1 on cyclin B1 levels, proliferation, and apoptosis were assayed in human HER2-positive breast cancer explants.Results: 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. Cyclin B1 knockdown by siRNA in parental cells induced T-DM1 resistance, while increased levels of cyclin B1 by silencing cdc20 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.Conclusions: 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. Clin Cancer Res; 23(22); 7006-19. ©2017 AACR.
dc.description.sponsorship This work was supported by ISCiii (CIBERONC CB16/12/00481, RD12/0036/0051, RD12/0036/0070, RD12/0036/0003, PIE15/00008, PI13/00864, PI15/00146, PI15/00934, PI15/01617, PT13/0010/0005), Generalitat de Catalunya (2014 SGR 740), and the "Xarxa de Bancs de tumors sponsored by Pla Director d'Oncologia de Catalunya (XBTC). MINECO through BFU2015-71371-R grant supported work in A. Pandiella's laboratory. Our work was supported by the EU through the regional funding development program (FEDER). P. González-Alonso was supported by Fundación Conchita Rábago de Jiménez Díaz grant.
dc.format.mimetype application/pdf
dc.language.iso eng
dc.publisher American Association for Cancer Research (AACR)
dc.relation.ispartof Clinical Cancer Research. 2017 Nov 15;23(22):7006-19
dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1078-0432.CCR-17-0696
dc.subject.other Mama -- Càncer -- Tractament
dc.title Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.1158/1078-0432.CCR-17-0696
dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-71371-R
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/acceptedVersion

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