Defective Cyclin B1 Induction in Trastuzumab-emtansine (T-DM1) Acquired Resistance in HER2-positive Breast Cancer
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- MohammadA Sabbaghi
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Gabriel Gil-Gómez
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Cristina Guardia
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Sonia Servitja
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Oriol Arpí
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Sara García-Alonso
- 3Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC-CIBERONC, Salamanca, Spain.
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- Silvia Menendez
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Montserrat Arumi-Uria
- 4Pathology Department, Hospital del Mar, Barcelona, Spain.
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- Laia Serrano
- 4Pathology Department, Hospital del Mar, Barcelona, Spain.
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- Marta Salido
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Aura Muntasell
- 5Immunity and infection Laboratory, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Maria Martínez-García
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Sandra Zazo
- 6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
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- Cristina Chamizo
- 6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
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- Paula González-Alonso
- 6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
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- Juan Madoz-Gúrpide
- 6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
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- Pilar Eroles
- 7INCLIVA Biomedical Research Institute, Valencia, Spain.
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- Joaquin Arribas
- 8Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO)-CIBERONC, Barcelona, Spain.
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- Ignasi Tusquets
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Ana Lluch
- 11Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.
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- Atanasio Pandiella
- 3Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC-CIBERONC, Salamanca, Spain.
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- Federico Rojo
- 6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
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- Ana Rovira
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
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- Joan Albanell
- 1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
Abstract
<jats:title>Abstract</jats:title><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>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.</jats:p><jats:p>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.</jats:p>
Journal
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- Clinical Cancer Research
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Clinical Cancer Research 23 (22), 7006-7019, 2017-11-14
American Association for Cancer Research (AACR)
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Details 詳細情報について
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- CRID
- 1363951796148543616
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- ISSN
- 15573265
- 10780432
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- Data Source
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- Crossref