Identification of therapeutic targets in ovarian cancer through active tyrosine kinase profiling

Abstract

// Juan Carlos Montero 1, * , Sara García-Alonso 1, * , Alberto Ocaña 2 , Atanasio Pandiella 1 1 Instituto de Biología Molecular y Celular del Cáncer. CSIC-Universidad de Salamanca, Spain 2 Medical Oncology Unit, University Hospital of Albacete, Spain * These authors have contributed equally to this work Correspondence to: Atanasio Pandiella, e-mail: atanasio@usal.es Keywords: tyrosine kinases, HER2, ovarian cancer, T-DM1 Received: February 23, 2015      Accepted: July 31, 2015      Published: August 13, 2015 ABSTRACT The activation status of a set of pro-oncogenic tyrosine kinases in ovarian cancer patient samples was analyzed to define potential therapeutic targets. Frequent activation of HER family receptor tyrosine kinases, especially HER2, was observed. Studies in ovarian cancer cell lines confirmed the activation of HER2. Moreover, knockdown of HER2 caused a strong inhibition of their proliferation. Analyses of the action of agents that target HER2 indicated that the antibody drug conjugate trastuzumab-emtansine (T-DM1) caused a substantial antitumoral effect in vivo and in vitro , and potentiated the action of drugs used in the therapy of ovarian cancer. T-DM1 provoked cell cycle arrest in mitosis, and caused the appearance of aberrant mitotic spindles in cells treated with the drug. Biochemical experiments confirmed accumulation of the mitotic markers phospho-Histone H3 and phospho-BUBR1 in cells treated with the drug. Prolonged treatment of ovarian cancer cells with T-DM1 provoked the appearance of multinucleated cells which later led to cell death. Together, these data indicate that HER2 represents an important oncogene in ovarian cancer, and suggest that targeting this tyrosine kinase with T-DM1 may be therapeutically effective, especially in ovarian tumors with high content of HER2.