PF372 INHIBITION OF BROMODOMAIN AND EXTRA‐TERMINAL (BET) PROTEINS INCREASES SENSITIVITY TO VENETOCLAX IN CHRONIC LYMPHOCYTIC LEUKEMIA

Abstract

Background:The development of drugs able to target BTK, PI3k‐delta and Bcl2 has dramatically improved Chronic Lymphocytic Leukemia therapies. However, resistant cases to these drugs have already been reported due to non‐recurrent changes in oncogenic pathways and genes expression signatures.Aims:In this study, we investigated thecooperative role of Venetoclax and the JQ1 inhibitor in order to prevent and eventually overcome the development of resistance to Bcl‐2 inhibitor.Methods:MEC‐1/EHEB cells lines and primary CD19 positive lymphocytes from CLL patients were treated with BET inhibitor JQ1 and venetoclax. Cell lines were screened for cell viability upon treatment with Venetoclax, JQ1and the combination of the two. Responses were measured as apoptosis induction (Annexin V), cell growth arrest and cell‐cycle accumulation. Furthermore, Western Blot analysis RT‐PCR and Immunofluorescence were used to determine expression of Brd members and BCL‐2 pathway components.Results:We demonstrated that treatment with BCL2 inhibitor is associated with a rapid emergence of resistant clones. Compared with each agent alone, cotreatment with JQ1 and venetoclax improved apoptosis in CLL cell lines and of the in vitro isolate primary CD19+ lymphocytes. Additionally, cotreatment could prevent the development of resistant clones. Lastly, JQ1 is also able to restore sensitiveness to venetoclax in venetoclax‐resistant CLL cell lines.Summary/Conclusion:Our findings indicated that cotreatment with JQ1 and BCL2 inhibitor synergistically induced apoptosis and eventually, prevent the development of resistant clones. Further knowledge is key to development of combinatorial treatment strategies with this two drugs.