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 Alica
  • dc.contributor.author Gil Gómez, Gabrielca
  • dc.contributor.author Guardia Laguarta, Cristinaca
  • dc.contributor.author Servitja Tormo, Soniaca
  • dc.contributor.author Arpí Llucià, Oriolca
  • dc.contributor.author Menendez Romero, Silviaca
  • dc.contributor.author Arumí, Montserratca
  • dc.contributor.author Serrano, Laiaca
  • dc.contributor.author Salido Galeote, Martaca
  • dc.contributor.author Muntasell i Castellví, Aura, 1972-ca
  • dc.contributor.author Martínez-García, Mariaca
  • dc.contributor.author Tusquets Trias de Bes, Ignacioca
  • dc.contributor.author Rovira Guerín, Anaca
  • dc.contributor.author Albanell Mestres, Joanca
  • dc.date.accessioned 2018-05-07T07:52:48Z
  • dc.date.issued 2017
  • 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.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.doi http://dx.doi.org/10.1158/1078-0432.CCR-17-0696
  • dc.identifier.issn 1078-0432
  • dc.identifier.uri http://hdl.handle.net/10230/34570
  • dc.language.iso eng
  • dc.publisher American Association for Cancer Research (AACR)ca
  • dc.relation.ispartof Clinical Cancer Research. 2017 Nov 15;23(22):7006-19
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2015-71371-R
  • dc.rights © American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1078-0432.CCR-17-0696
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.subject.other Mama -- Càncer -- Tractament
  • dc.title Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancerca
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/acceptedVersion

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