Sabbaghi Mehrjardi, Mohammad AliGil Gómez, GabrielGuardia Laguarta, CristinaServitja Tormo, SoniaArpí Llucià, OriolMenendez Romero, SilviaArumí, MontserratSerrano, LaiaSalido Galeote, MartaMuntasell i Castellví, Aura, 1972-Martínez-García, MariaTusquets Trias de Bes, IgnacioRovira Guerín, AnaAlbanell Mestres, Joan2018-05-072017Sabbaghi 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-17-06961078-0432http://hdl.handle.net/10230/34570Purpose: 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.application/pdfeng© American Association for Cancer Research (AACR) http://dx.doi.org/10.1158/1078-0432.CCR-17-0696Mama -- Càncer -- Tractamentinfo:eu-repo/semantics/articlehttp://dx.doi.org/10.1158/1078-0432.CCR-17-0696info:eu-repo/semantics/openAccess