Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Clinical cancer research, 2017-11, Vol.23 (22), p.7006-7019

Ort / Verlag

United States: American Association for Cancer Research Inc

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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. .