Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer

Virginie Maire (1, 1) , Fariba Nemati (1, 1) , Marion Richardson (1, 1) , Anne Vincent-Salomon (1, 2) , Bruno Tesson (1, 1, 3) , Guillem Rigaill (4, 1, 1, 3) , Eleonore Gravier (1, 3, 5) , Berengere Marty-Prouvost (1, 1) , Leanne de Koning (1, 1, 6) , Guillaume Lang (1, 1) , David Gentien (1, 7) , Aurelie Dumont (1, 1) , Emmanuel Barillot (3) , Elisabetta Marangoni (1, 1) , Didier Decaudin (1, 1, 8) , Sergio Roman-Roman (1) , Alain Pierre (9) , Francisco Cruzalegui (9) , Stephane Depil (9) , Gordon C. Tucker (9) , Thierry Dubois (10, 1, 1)

1 CHU Pitié-Salpêtrière [AP-HP]
2 U830 - Unité de génétique et biologie des cancers
3 Cancer et génome: Bioinformatique, biostatistiques et épidémiologie d'un système complexe
4 MIA-Paris - Mathématiques et Informatique Appliquées
5 Dept Biostat
6 Dept Reverse Phase Prot Array Platform
7 Platform Mol Biol Facil
8 Dept Med Oncol
9 Oncol Res & Dev Unit
10 Ctr Rech, Equipe Biol Canc Sein, Dept Rech Translat

Breast cancers are composed of molecularly distinct subtypes with different clinical outcomes and responses to therapy. To discover potential therapeutic targets for the poor prognosis-associated triple-negative breast cancer (TNBC), gene expression profiling was carried out on a cohort of 130 breast cancer samples. Polo-like kinase 1 (PLK1) was found to be significantly overexpressed in TNBC compared with the other breast cancer subtypes. High PLK1 expression was confirmed by reverse phase protein and tissue microarrays. In triple-negative cell lines, RNAi-mediated PLK1 depletion or inhibition of PLK1 activity with a small molecule (BI-2536) induced an increase in phosphorylated H2AX, G(2)-M arrest, and apoptosis. A soft-agar colony assay showed that PLK1 silencing impaired clonogenic potential of TNBC cell lines. When cells were grown in extracellular matrix gels (Matrigel), and exposed to BI-2536, apoptosis was observed specifically in TNBC cancerous cells, and not in a normal cell line. When administrated as a single agent, the PLK1 inhibitor significantly impaired tumor growth in vivo in two xenografts models established from biopsies of patients with TNBC. Most importantly, the administration of BI-2536, in combination with doxorubicin + cyclophosphamide chemotherapy, led to a faster complete response compared with the chemotherapy treatment alone and prevented relapse, which is the major risk associated with TNBC. Altogether, our observations suggest PLK1 inhibition as an attractive therapeutic approach, in association with conventional chemotherapy, for the management of patients with TNBC. Cancer Res; 73(2); 813-23. (C) 2012 AACR.

Mots clés: GENE-EXPRESSION; TP53 MUTATION; PLK1; SCREEN; MAMMALIAN-CELLS; INITIATING CELLS; CELL-LINES; PHASE-I; INHIBITOR BI 2536; ADVANCED SOLTUMORS

Domaines: Sciences du Vivant [q-bio]

Virginie Maire, Fariba Nemati, Marion Richardson, Anne Vincent-Salomon, Bruno Tesson, et al.. Polo-like Kinase 1: A Potential Therapeutic Option in Combination with Conventional Chemotherapy for the Management of Patients with Triple-Negative Breast Cancer. Cancer Research, 2013, 73 (2), pp.813 - 823. ⟨10.1158/0008-5472.CAN-12-2633⟩. ⟨hal-01190661⟩