An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy
An IRAK1-PIN1 signalling axis drives intrinsic tumour resistance to radiation therapy
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DOI：
10.1038/s41556-018-0260-7
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发表时间：
2019-02-01
影响因子：
21.3
通讯作者：
Sidi, Samuel
中科院分区：
文献类型：
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作者：
Liu, Peter H.;Shah, Richa B.;Sidi, Samuel
克服肿瘤放射抗药性(R-RT)的药物策略仍然受到传统放射增敏剂(例如铂)的单剂毒性和缺乏有针对性的替代品的限制。在对p53突变斑马鱼在非辐射野生动物中耐受时恢复辐射敏感性的化合物的筛选中，我们鉴定了苯并咪唑驱虫药奥芬达唑。令人惊讶的是，奥芬达唑通过抑制IRAK1发挥作用，到目前为止，IRAK1是一种与白细胞介素1受体(IL-1R)和Toll样受体(TLR)免疫反应有关的激酶。IRAK1驱动R-RT的途径包括IRAK4和TRAF6，但不包括IL-1R/TLR-IRAK接头MyD88。辐射激活的IRAK1不是刺激核因子-kappa B，而是阻止由PIDDosome复合体(包括PIDD、RAIDD和caspase-2)介导的细胞凋亡。在肿瘤模型中，用IRAK1抑制剂对抗这一途径抑制了R-RT，在肿瘤模型中，TP53突变预测了R-RT。此外，IRAK1抑制剂与Pin1的抑制剂协同作用，Pin1是一种对病原体和电离辐射的反应中激活IRAK1必不可少的脯氨基异构酶。这些数据表明，IRAK1辐射反应通路是合理的放化疗靶点。
Drug-based strategies to overcome tumour resistance to radiotherapy (R-RT) remain limited by the single-agent toxicity of traditional radiosensitizers (for example, platinums) and a lack of targeted alternatives. In a screen for compounds that restore radiosensitivity in p53 mutant zebrafish while tolerated in non-irradiated wild-type animals, we identified the benzimidazole anthelmintic oxfendazole. Surprisingly, oxfendazole acts via the inhibition of IRAK1, a kinase thus far implicated in interleukin-1 receptor (IL-1R) and Toll-like receptor (TLR) immune responses. IRAK1 drives R-RT in a pathway involving IRAK4 and TRAF6 but not the IL-1R/TLR-IRAK adaptor MyD88. Rather than stimulating nuclear factor-kappa B, radiation-activated IRAK1 prevented apoptosis mediated by the PIDDosome complex (comprising PIDD, RAIDD and caspase-2). Countering this pathway with IRAK1 inhibitors suppressed R-RT in tumour models derived from cancers in which TP53 mutations predict R-RT. Moreover, IRAK1 inhibitors synergized with inhibitors of PIN1, a prolyl isomerase essential for IRAK1 activation in response to pathogens and, as shown here, in response to ionizing radiation. These data identify an IRAK1 radiation-response pathway as a rational chemoradiation therapy target.