The BTK/PI3K/BRD4 axis inhibitor SRX3262 overcomes Ibrutinib resistance in mantle cell lymphoma
Dhananjaya Pal,
Kendra R. Vann,
Shweta Joshi,
Namood E. Sahar,
Guillermo A. Morales,
Dalia El-Gamal,
Tatiana G. Kutateladze,
Donald L. Durden
Affiliations
Dhananjaya Pal
Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics Computational Chemistry, College of Medicine University of Nebraska Medical Center, Omaha, NE, USA
Kendra R. Vann
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA
Shweta Joshi
Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA
Namood E. Sahar
Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics Computational Chemistry, College of Medicine University of Nebraska Medical Center, Omaha, NE, USA
Guillermo A. Morales
SignalRx Pharmaceuticals, Inc., Cumming, GA, USA
Dalia El-Gamal
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
Tatiana G. Kutateladze
Department of Pharmacology, University of Colorado School of Medicine, Aurora, CO, USA; Corresponding author
Donald L. Durden
Division of Hematology and Oncology, Department of Pediatrics, Moores Cancer Center, University of California San Diego, La Jolla, CA, USA; Department of Pediatrics Computational Chemistry, College of Medicine University of Nebraska Medical Center, Omaha, NE, USA; SignalRx Pharmaceuticals, Inc., Cumming, GA, USA; Corresponding author
Summary: Mantle cell lymphoma (MCL) is an aggressive subtype of non-Hodgkin's lymphoma and one of the most challenging blood cancers to combat due to frequent relapse after treatment. Here, we developed the first-in-class BTK/PI3K/BRD4 axis inhibitor SRX3262, which simultaneously blocks three interrelated MCL driver pathways – BTK, PI3K-AKT-mTOR and MYC. SRX3262 concomitantly binds to BTK, PI3K, and BRD4, exhibits potent in vitro and in vivo activity against MCL, and overcomes the Ibrutinib resistance resulting from the BTK-C481S mutation. Our results reveal that SRX3262 inhibits IgM-induced BTK and AKT phosphorylation and abrogates binding of BRD4 to MYC loci. SRX3262 promotes c-MYC destabilization, induces cell cycle arrest and apoptosis, and shows antitumor activity in in vivo xenograft models. Together, our study provides mechanistic insights and rationale for the use of the triple BTK/PI3K/BRD4 activity inhibitors as a new approach to treat MCL.
