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

  • MohammadA Sabbaghi
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Gabriel Gil-Gómez
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Cristina Guardia
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Sonia Servitja
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Oriol Arpí
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Sara García-Alonso
    3Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC-CIBERONC, Salamanca, Spain.
  • Silvia Menendez
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Montserrat Arumi-Uria
    4Pathology Department, Hospital del Mar, Barcelona, Spain.
  • Laia Serrano
    4Pathology Department, Hospital del Mar, Barcelona, Spain.
  • Marta Salido
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Aura Muntasell
    5Immunity and infection Laboratory, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Maria Martínez-García
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Sandra Zazo
    6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
  • Cristina Chamizo
    6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
  • Paula González-Alonso
    6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
  • Juan Madoz-Gúrpide
    6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
  • Pilar Eroles
    7INCLIVA Biomedical Research Institute, Valencia, Spain.
  • Joaquin Arribas
    8Preclinical Research Program, Vall d'Hebron Institute of Oncology (VHIO)-CIBERONC, Barcelona, Spain.
  • Ignasi Tusquets
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Ana Lluch
    11Oncology and Hematology Department, Hospital Clínico Universitario-CIBERONC, Valencia, Spain.
  • Atanasio Pandiella
    3Centro de Investigación del Cáncer, Universidad de Salamanca-CSIC-CIBERONC, Salamanca, Spain.
  • Federico Rojo
    6Pathology Department, IIS-Fundación Jiménez Díaz- CIBERONC, Madrid, Spain.
  • Ana Rovira
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.
  • Joan Albanell
    1Cancer Research Program, IMIM (Hospital del Mar Research Institute), Barcelona, Spain.

抄録

<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>

収録刊行物

  • Clinical Cancer Research

    Clinical Cancer Research 23 (22), 7006-7019, 2017-11-14

    American Association for Cancer Research (AACR)

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