Endometrial cancer (EC) is the fourth most common cancer in women. Advanced-stage EC has limited treatment options with a poor prognosis. There is an unmet need for the identification of actionable drivers for the development of targeted therapies in EC. Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a major role in cancer progression, metastasis, stemness, and therapy resistance. However, little is known about the functional significance of the LIF/LIFR axis in EC progression. In this study using endometrial tumor tissue arrays, we identified that expression of LIF, LIFR is upregulated in EC. Knockout of LIFR using CRISPR/Cas9 in two different EC cells resulted in a significant reduction of their cell viability and cell survival. In vivo studies demonstrated that LIFR-KO significantly reduced EC xenograft tumor growth. Treatment of established and primary patient-derived EC cells with a novel LIFR inhibitor, EC359 resulted in the reduction of cell viability with an IC₅₀ in the range of 20–100 nM and induction of apoptosis. Further, treatment with EC359 reduced the spheroid formation of EC cancer stem cells and reduced the levels of cancer stem cell markers SOX2, OCT4, NANOG, and Axin2. Mechanistic studies demonstrated that EC359 treatment attenuated the activation of LIF-LIFR driven pathways, including STAT3 and AKT/mTOR signaling in EC cells. Importantly, EC359 treatment resulted in a significant reduction of the growth of EC patient-derived explants ex vivo, EC cell line-derived xenografts, and patient-derived xenografts in vivo. Collectively, our work revealed the oncogenic potential of the LIF/LIFR axis in EC and support the utility of LIFR inhibitor, EC359, as a novel targeted therapy for EC via the inhibition of LIF/LIFR oncogenic signaling.

子宫内膜癌（EC）是女性第四大常见癌症。晚期 EC 的治疗选择有限，预后较差。确定 EC 靶向治疗开发的可行驱动因素的需求尚未得到满足。白血病抑制因子受体 (LIFR) 及其配体 LIF 在癌症进展、转移、干细胞性和治疗耐药性中发挥着重要作用。然而，人们对 LIF/LIFR 轴在 EC 进展中的功能意义知之甚少。在这项使用子宫内膜肿瘤组织芯片的研究中，我们发现 LIF、LIFR 的表达在 EC 中上调。在两种不同的 EC 细胞中使用 CRISPR/Cas9 敲除 LIFR 导致细胞活力和细胞存活率显着降低。体内研究表明，LIFR-KO 显着降低了 EC 异种移植肿瘤的生长。用新型 LIFR 抑制剂 EC359 处理已建立的原代患者来源的 EC 细胞，导致细胞活力降低（IC ₅₀在 20-100 nM 范围内）并诱导细胞凋亡。此外，EC359 治疗减少了 EC 癌症干细胞的球体形成，并降低了癌症干细胞标志物 SOX2、OCT4、NANOG 和 Axin2 的水平。机制研究表明，EC359 治疗减弱了 LIF-LIFR 驱动通路的激活，包括 EC 细胞中的 STAT3 和 AKT/mTOR 信号传导。重要的是，EC359治疗导致EC患者来源的离体外植体、EC细胞系来源的异种移植物和患者来源的体内异种移植物的生长显着减少。 总的来说，我们的工作揭示了 LIF/LIFR 轴在 EC 中的致癌潜力，并支持 LIFR 抑制剂 EC359 通过抑制 LIF/LIFR 致癌信号作为 EC 的新型靶向疗法。