IRAK1 and IRAK4 as emerging therapeutic targets in hematologic malignancies

Purpose of review Cell intrinsic and extrinsic perturbations to inflammatory signaling pathways are a hallmark of development and progression of hematologic malignancies. The interleukin 1 receptor-associated kinases (IRAKs) are a family of related signaling intermediates (IRAK1, IRAK2, IRAK3, IRAK4) that operate at the nexus of multiple inflammatory pathways implicated in the hematologic malignancies. In this review, we explicate the oncogenic role of these kinases and review recent therapeutic advances in the dawning era of IRAK-targeted therapy. Recent findings Emerging evidence places IRAK signaling at the confluence of adaptive resistance and oncogenesis in the hematologic malignancies and solid tissue tumors. Preclinical investigations nominate the IRAK kinases as targetable molecular dependencies in diverse cancers. IRAK-targeted therapies that have matriculated to early phase trials are yielding promising preliminary results. However, studies of IRAK kinase signaling continue to defy conventional signaling models and raise questions as to the design of optimal treatment strategies. Efforts to refine IRAK signaling mechanisms in the malignant context will inspire deliberate IRAK-targeted drug development and informed combination therapy.

Automated summary

Cell intrinsic and extrinsic perturbations to inflammatory signaling pathways play a crucial role in the development and progression of hematologic malignancies. The interleukin 1 receptor-associated kinases (IRAKs) are a family of signaling intermediates that operate at the intersection of multiple inflammatory pathways implicated in these malignancies. Recent studies have shown that IRAK signaling is involved in adaptive resistance and oncogenesis in both hematologic and solid tissue tumors. Targeted therapies against IRAK kinases have shown promising preliminary results in early phase trials, but the signaling mechanisms of IRAK kinases continue to raise questions about optimal treatment strategies. Efforts to understand these mechanisms will lead to the development of targeted drugs and combination therapy for IRAK-related malignancies.