TY - JOUR T1 - Dual Inhibiton of Bruton’s Tyrosine Kinase and Phosphoinositide-3-Kinase p110δ as a Therapeutic Approach to Treat non-Hodgkin’s B cell Malignancies JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.116.238022 SP - jpet.116.238022 AU - Jennifer Alfaro AU - Felipe Perez de Arce AU - Sebastian Belmar AU - Glenda Fuentealba AU - Patricio Avila AU - Gonzalo Ureta AU - Camila Flores AU - Claudia Acuna AU - Luz Delgado AU - Diana Gaete AU - Brahmam Pujala AU - Anup Barde AU - Anjan K. Nayak AU - TVR Upendra AU - Dhananjay Patel AU - Shailender Chauhan AU - Vijay K. Sharma AU - Stacy Kanno AU - Ramona G. Almirez AU - David T. Hung AU - Sarvajit Chakravarty AU - Roopa Rai AU - Sebastian Bernales AU - Kevin P. Quinn AU - Son M. Pham AU - Emma McCullagh Y1 - 2017/01/01 UR - http://jpet.aspetjournals.org/content/early/2017/03/15/jpet.116.238022.abstract N2 - Although new targeted therapies such as ibrutinib and idelalisib have made a large impact on non-Hodgkin's lymphoma (NHL) patients, the disease is often fatal because patients are initially resistant to these targeted therapies or because they eventually develop resistance. New drugs and treatments are necessary for these patients. One attractive approach is to inhibit multiple parallel pathways that drive the growth of these hematologic tumors and possibly prolonging the duration of the response and reducing resistance. Early clinical trials have tested this approach by dosing two drugs in combination in NHL patients. We have discovered a single molecule MDVN1003 that inhibits Bruton's tyrosine kinase (BTK) and phosphatidylinositol-3-kinase delta (PI3Kδ), two proteins regulated by the B cell receptor (BCR) that drive the growth of many NHLs. In this report, we show that this dual inhibitor prevents the activation of B cells and inhibits the phosphorylation of protein kinase B (AKT) and extracellular signal-regulated kinase 1/2 (ERK 1/2), two downstream mediators that are important for this process. Additionally, MDVN1003 induces cell death in a B cell lymphoma cell line but not in an irrelevant erythroblast cell line. Importantly, we found that this orally bioavailable dual inhibitor reduced tumor growth in a B cell lymphoma xenograft model more effectively than either ibrutinib or idelalisib. Taken together these results suggest that dual inhibition of these two key pathways by a single molecule could be a viable approach for treatment of NHL patients. ER -