Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer
Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer
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DOI：
10.1038/s41388-018-0156-9
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发表时间：
2018-07-05
期刊：
影响因子：
8
通讯作者：
Langenfeld, John
中科院分区：
文献类型：
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作者：
Newman, Jenna H.;Augeri, David J.;Langenfeld, John
BMP受体抑制剂通过下调抗凋亡蛋白XIAP、pTAK1和Id1-Id3诱导癌细胞死亡。然而，目前最有效的BMP受体抑制剂DMH2由于代谢不稳定和较差的药代动力学，在体内不能下调BMP信号。我们确定了DMH2代谢不稳定的位点，并设计了一种新的BMP受体抑制剂JL5。我们发现JL5在肿瘤异种移植物中具有更大的分布体积并抑制Id1和pTak1的表达。此外，我们在没有免疫细胞的异种移植小鼠模型和过继转移的人类免疫细胞的人源化小鼠模型中证明了jl5诱导的肿瘤细胞死亡和肿瘤消退。在人源化小鼠中，JL5还能诱导肿瘤微环境中免疫细胞的浸润。我们的研究表明，BMP信号通路在体内是可靶向的，BMP受体抑制剂可以作为一种治疗癌症患者的药物。
BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients.