Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center.
Department of Cancer Biology.
Curr Opin Hematol. 2022 Jan 1;29(1):8-19. doi: 10.1097/MOH.0000000000000693.
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.
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.
细胞内和细胞外炎症信号通路的改变是血液恶性肿瘤发生和发展的标志。白细胞介素 1 受体相关激酶（IRAKs）是一组相关的信号转导介质（IRAK1、IRAK2、IRAK3、IRAK4），它们位于多种炎症途径的交汇点，这些炎症途径与血液恶性肿瘤有关。在这篇综述中，我们阐述了这些激酶的致癌作用，并回顾了 IRAK 靶向治疗这一新兴领域的最新治疗进展。
新出现的证据表明 IRAK 信号在血液恶性肿瘤和实体组织肿瘤的适应性耐药和致癌作用中处于交汇点。临床前研究将 IRAK 激酶指定为多种癌症的可靶向分子依赖性。
已经进入早期临床试验的 IRAK 靶向治疗正在产生有希望的初步结果。然而，IRAK 激酶信号的研究继续挑战传统的信号模型，并提出了关于最佳治疗策略设计的问题。努力在恶性环境中细化 IRAK 信号机制将激发有针对性的 IRAK 靶向药物开发和明智的联合治疗。
