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.
Highlights
Ovarian cancer represents the leading cause of death from gynecological malignancies in western countries [1]
Given the relevance of tyrosine kinases in cancer initiation/progression and the benefits of their targeting in other oncological diseases [26], we evaluated the activation status of several tyrosine kinases in tumor samples surgically resected from patients with ovarian cancer
If HER2 is important in the pathophysiology of these tumors, a substantial proportion of ovarian cancer patients could benefit from the targeting of HER2
Summary
Ovarian cancer represents the leading cause of death from gynecological malignancies in western countries [1]. Intense efforts are being carried out to define potential molecular targets that may augment survival of patients with ovarian cancer. In this respect, several reports have identified potential therapeutic targets and the efficacy of treatments against such targets is being analyzed in clinical trials in various phases of development [1]. Several reports have identified potential therapeutic targets and the efficacy of treatments against such targets is being analyzed in clinical trials in various phases of development [1] Among such experimental treatments, agents acting on tyrosine kinases have received special attention. Phase II trials have reported negative results in patients treated with imatinib, which targets both PDGFR and c-Kit [1]
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