Oncotarget

Research Papers:

Therapeutic potential of ERK5 targeting in triple negative breast cancer

María Jesús Ortiz-Ruiz _, Stela Álvarez-Fernández, Tracy Parrott, Sara Zaknoen, Francis J. Burrows, Alberto Ocaña, Atanasio Pandiella and Azucena Esparís-Ogando

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2014; 5:11308-11318. https://doi.org/10.18632/oncotarget.2324

Metrics: PDF 3023 views  |   HTML 3055 views  |   ?  


Abstract

María Jesús Ortiz-Ruiz1, Stela Álvarez-Fernández1, Tracy Parrott2, Sara Zaknoen2, Francis J. Burrows2, Alberto Ocaña3, Atanasio Pandiella1, Azucena Esparís-Ogando1

1Instituto de Biología Molecular y Celular del Cáncer, CSIC-IBSAL-Universidad de Salamanca, Spain

2Tragara Pharmaceuticals, Carlsbad, CA, USA

3Hospital Universitario de Albacete, and AECC Unit, Spain

Correspondence to:

Azucena Esparís-Ogando, e-mail: [email protected]

Keywords: breast cancer, kinase inhibitor, ERK5.

Received: April 21, 2014     Accepted: August 06, 2014     Published: November 04, 2014

ABSTRACT

Triple negative breast cancers (TNBCs) account for 15% of all breast cancers, and represent one of the most aggressive forms of the disease, exhibiting short relapse-free survival. In contrast to other breast cancer subtypes, the absence of knowledge about the etiopathogenic alterations that cause TNBCs force the use of chemotherapeutics to treat these tumors. Because of this, efforts have been devoted with the aim of incorporating novel therapies into the clinical setting. Kinases play important roles in the pathophysiology of several tumors, including TNBC. Since expression of the MAP kinase ERK5 has been linked to patient outcome in breast cancer, we analyzed the potential value of its targeting in TNBC. ERK5 was frequently overexpressed and active in samples from patients with TNBC, as well as in explants from mice carrying genetically-defined TNBC tumors. Moreover, expression of ERK5 was linked to a worse prognosis in TNBC patients. Knockdown experiments demonstrated that ERK5 supported proliferation of TNBC cells. Pharmacological inhibition of ERK5 with TG02, a clinical stage inhibitor which targets ERK5 and other kinases, inhibited cell proliferation by blocking passage of cells through G1 and G2, and also triggered apoptosis in certain TNBC cell lines. TG02 had significant antitumor activity in a TNBC xenograft model in vivo, and also augmented the activity of chemotherapeutic agents commonly used to treat TNBC. Together, these data indicate that ERK5 targeting may represent a valid strategy against TNBC, and support the development of trials aimed at evaluating the clinical effectiveness of drugs that block this kinase.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 2324