Activating Transcription Factor 3 Expression as a Marker of Response to the Histone Deacetylase Inhibitor Pracinostat
Menée in vitro et in vivo, cette étude suggère l'intérêt de mesurer l'expression du facteur de transcription ATF3 pour prédire la réponse au pracinostat dans le traitement des patients atteints d'un cancer de la vessie
Improved treatment strategies are required for bladder cancer, due to frequent recurrence of low-grade tumors and poor survival rate from high-grade tumors with current therapies. Histone deacetylase inhibitors (HDACi), approved as single agents for specific lymphomas, have shown promising preclinical results in solid tumors but could benefit from identification of biomarkers for response. Loss of activating transcription factor 3 (ATF3) expression is a feature of bladder tumor progression, and correlates with poor survival. We investigated the utility of measuring ATF3 expression as marker of response to the HDACi Pracinostat in bladder cancer models. Pracinostat treatment of bladder cancer cell lines reactivated expression of ATF3, correlating with significant alteration in proliferative, migratory and anchorage-dependent growth capacities. Pracinostat also induced growth arrest at the G0/G1 cell cycle phase, coincident with activation of tumor suppressor genes. In mouse xenograft bladder cancer models, Pracinostat treatment significantly reduced tumor volumes compared to controls, accompanied by re-expression of ATF3 in non-proliferating cells from early to late stage of therapy, and in parallel induced anti-angiogenesis and apoptosis. Importantly, cells in which ATF3 expression was depleted were less sensitive to Pracinostat treatment in vitro, exhibiting significantly higher proliferative and migratory properties. In vivo, control xenograft tumors were significantly more responsive to treatment than ATF3 knockdown xenografts. Thus reactivation of ATF3 is an important factor in determining sensitivity to Pracinostat treatment, both in vitro and in vivo, and could serve as a potential biomarker of response, and provide a rationale for therapeutic utility in HDACi-mediated treatments for bladder cancer.
Molecular Cancer Therapeutics , résumé, 2016