NOXA IS A CRITICAL DETERMINANT OF SENSITIVITY TO THE BH3-MIMETICS ABT-263 AND WEHI-539 IN PATIENT-DERIVED GLIOMA STEM CELLS

GERMÁN NOGUEIRAS; OLIVIA MORRIS HANON; LEONARDO ROMORINI; VERÓNICA ALEJANDRA FURMENTO; LUCÍA CANEDO; CAROLINA PEREZ CASTRO; GUSTAVO E. SEVLEVER; MARÍA E. SCASSA; GUILLERMO A. VIDELA RICHARDSON

Congreso; LXIII Reunión Anual. Sociedad Argentina de Investigación Clínica (SAIC); 2018

Glioblastoma multiforme is one of the most malignant types of central nervous system tumors. Despite advances in treatments it remains largely incurable. This recurrence is attributed to the presence of a highly resistant subpopulation of tumor cells named glioma stem cells. Defective or inefficient apoptosis is an acquired hallmark of cancer cells. Thus, a thorough understanding of apoptosis resistance mechanisms is imperative to unravel novel drug targets for the design of more effective therapies. The BH3-only proteins of the Bcl-2 family can trigger apoptosis by binding to the pro-survival members of this family and neutralizing their activity. This concept has prompted the development of small molecules capable of mimicking BH3-only proteins leading to apoptosis, and thus, sensitizing cancer cells to treatments. Herein, we exposed five patient-derived glioma stem cell lines to routinely used chemotherapeutic drugs (temozolomide, lomustine and vincristine) and BH-3 mimetics (ABT-263 and WEHI-539). Viability assays revealed that the combination of BH3 mimetics that target Bcl-xL with chemotherapeutic drugs led to a marked increase in cell death compared to that triggered by each drug alone. Notably, one cell line resulted particularly sensitive to these combination therapies and this sensitivity correlated with the expression of the BH3-only protein NOXA. ABT-263 not only increased the degree of cell death but also induced NOXA mRNA levels as judged by RT-qPCR analysis. Moreover, we observed that siRNA-mediated downregulation of NOXA protected glioma stem cells from BH3-mimetic-induced cell death. These results indicate that NOXA contributes to glioma stem cell apoptosis and that its expression could represent a predictive biomarker of sensitivity to Bcl-xL inhibitors. Therefore, a proposed strategy to combat brain tumors that express NOXA would consist of combining Bcl-xL inhibitors with agents that potentiate NOXA activity.