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Defective cyclin B1 induction in trastuzumab-emtansine (T-DM1) acquired resistance in HER2-positive breast cancer

AuthorsSabbaghi, Mohammad A.; 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, Crsitina; Gonzalez-Alonso, Paula; Madoz-Gúrpide, Juan ; Eroles, Pilar; Arribas, Joaquín; Tusquets, Ignasi; Lluch, Ana; Pandiella, Atanasio ; Rojo, Federico; Rovira, Ana; Albanell, Joan
Issue Date2017
PublisherAmerican Association for Cancer Research
CitationClinical Cancer Research 23(22): 7006-7019 (2017)
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.
Identifiersdoi: 10.1158/1078-0432.CCR-17-0696
e-issn: 1557-3265
issn: 1078-0432
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