John M Hatcher, Shirong Liu, Xia Liu, Amanda Kofides, Alexa G Canning, Dominic Pizzarella, Nickolas Tsakmaklis, Maria L Guerrera, Christopher J Patterson, Alberto Guijosa, Prafulla Gokhale, Zachary R Hunter, Shayna R Sarosiek, Jorge J Castillo, Jinhua Wang, Sara J Buhrlage, Steven P Treon
Activating MYD88 mutations promote pro-survival signaling through divergent HCK/BTK and IRAK1/IRAK4 pathways, and persistent IRAK signaling may contribute to incomplete responses to BTK inhibitors. Here, we show that IRAK1 or IRAK4 knockdown reduced NFKB signaling and impaired MYD88 mutant lymphoma cell survival but, unexpectedly, enhanced ERK1/2 signaling, which was blocked by HCK/BTK inhibition. Knockdown and replacement studies further supported kinase-independent scaffold functions for IRAK1 and IRAK4. These findings motivated development of JH-XIII-05-01, a first-in-class dual IRAK1/IRAK4 degrader designed to eliminate both catalytic and scaffold-dependent IRAK signaling. JH-XIII-05-01 retained potent IRAK1/IRAK4 biochemical activity, induced degradation of both targets, and showed superior antiproliferative activity compared with its nondegrading parental inhibitor JH-XI-82-01. JH-XIII-05-01 also enhanced apoptosis and synergized with covalent and noncovalent BTK inhibitors, BTK degraders, and the BCL-2 inhibitor venetoclax. These findings support dual IRAK1/IRAK4 degradation as a strategy for targeting MYD88 mutant lymphomas.