Chemo-genetic evaluation of the mitotic kinesin CENP-E reveals a critical role in triple-negative breast cancer
A partir d'une analyse de l'expression de gènes dans un millier d'échantillons tumoraux prélevés sur des patientes atteintes d'un cancer du sein, puis menée sur des lignées cellulaires et à l'aide de xénogreffes, cette étude met en évidence des mécanismes suggérant l'intérêt d'un inhibiteur de la protéine CENP-E pour le traitement d'un cancer du sein triplement négatif
Breast cancer patients with tumors lacking the three diagnostic markers (ER, PR, HER2) are classified as triple-negative (primarily basal-like) and have poor prognosis because there is no disease-specific therapy available. To address this unmet medical need, gene expression analyses using over a thousand breast cancer samples were conducted which identified elevated centromere protein E (CENP-E) expression in the basal-a molecular subtype relative to other subtypes. CENP-E, a mitotic kinesin component of the spindle assembly checkpoint, is shown to be induced in basal-a tumor cell lines by the mitotic spindle inhibitor drug docetaxel. CENP-E knockdown by inducible shRNA reduces basal-a breast cancer cell viability. A potent, selective CENP-E inhibitor (PF-2771) was used to define the contribution of CENP-E motor function to basal breast cancer. Mechanistic evaluation of PF-2771 in basal-a tumor cells links CENP-E dependent molecular events (e.g. phosphorylation of histone H3 Ser-10; phospho-HH3-Ser10) to functional outcomes (e.g. chromosomal congression defects). Across a diverse panel of breast cell lines, CENP-E inhibition by PF-2771 selectively inhibits proliferation of basal breast cancer cell lines relative to pre-malignant ones and its response correlates with the degree of chromosomal instability. Pharmacokinetic-pharmacodynamic-efficacy analysis in a basal-a xenograft tumor model shows that PF-2771 exposure is well-correlated with increased phospho-HH3-Ser10 levels and tumor growth regression. Complete tumor regression is observed in a patient-derived, basal-a breast cancer xenograft tumor model treated with PF-2771. Tumor regression is also observed with PF-2771 in a taxane-resistant basal-a model. Taken together, CENP-E may be an effective therapeutic target for triple-negative/basal-a breast cancer patients.
http://mct.aacrjournals.org/content/early/2014/06/13/1535-7163.MCT-14-0083-T.abstract