EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer
EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer
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DOI：
10.1158/1535-7163.mct-18-1258
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发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Vadlamudi, Ratna K.
中科院分区：
文献类型：
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作者：
Viswanadhapalli, Suryavathi;Luo, Yiliao;Vadlamudi, Ratna K.
白血病抑制因子受体（LIFR）及其配体LIF在癌症进展、转移、干细胞维持和治疗抵抗中起关键作用。莱雷，我们描述了一种合理设计的LIFR的第一类抑制剂，EC 359，其直接与LIFR相互作用以有效地阻断LIF/LIFR相互作用。EC 359治疗在三阴性乳腺癌（TNBC）细胞系中表现出抗增殖作用，降低侵袭性和干性，并促进细胞凋亡。EC 359的活性依赖于LIF和LIFR的表达，并且用EC 359处理减弱了LIF/III R驱动的通路的激活，包括STAT 3、mTOR和AKT。同时，EC 359也有效阻断在LIF/LIFR界面相互作用的其他LIFR配体（CTF 1、CNTF和OSM）的信号传导。EC 359显著降低了TNBC异种移植物和患者来源的异种移植物（PDX）中的肿瘤进展，并降低了患者来源的原发性TNBC外植体中的增殖。EC 359具有独特的药理学优势，包括口服生物利用度和体内稳定性。总的来说，这些数据支持EC 359作为抑制LIFR致癌信号传导的新型靶向治疗剂。
Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. I lere, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and sternness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/III R-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patient-derived primary TNBC explants. EC359 exhibits distinct pharmacologic advantages, including oral bioavailability, and in vivo stability. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling.