子宫内膜癌(ECa)是最常见的女性妇科癌症。当比较子宫内膜癌的两种组织学亚型时,II型肿瘤在生物学上更具侵袭性,并且具有比I型肿瘤更差的预后。目前II型肿瘤的治疗无效,迫切需要新的靶向治疗。LIFR及其配体,LIF,已被证明在多种实体癌的进展和治疗耐药性中起关键作用。LIF/LIFR在II型ECa进展中的作用,另一方面,是未知的。我们研究了LIF/LIFR信号在II型ECa中的作用,并测试了新型小分子LIFR抑制剂EC359的功效,对抗II型ECa。对肿瘤数据库的分析揭示了生存率降低与白血病抑制因子(LIF)表达增加之间的相关性。提示在II型ECa中改变的LIF表达与不利的总体生存率之间存在潜在的联系。从细胞活力和集落形成测定获得的结果表明,与载体对照细胞相比,II型ECaLIFR敲低细胞的生长显著降低。此外,在原代和已建立的II型ECa细胞中,用EC359对LIF/LIFR轴的药理学抑制显着降低了细胞活力,细胞长期存活,和入侵,促进细胞凋亡。此外,EC359处理减少了由LIF/LIFR驱动的途径的激活,如AKT,mTOR,和STAT3。在两种不同的患者来源的体内异种移植模型和患者来源的离体器官中,EC359治疗显著抑制了肿瘤进展。总的来说,这些结果表明LIFR抑制剂EC359可能是治疗II型ECa的新的小分子治疗剂.
Endometrial cancer (ECa) is the most common female gynecologic cancer. When comparing the two histological subtypes of endometrial cancer, Type II tumors are biologically more aggressive and have a worse prognosis than Type I tumors. Current treatments for Type II tumors are ineffective, and new targeted therapies are urgently needed.
LIFR and its ligand, LIF, have been shown to play a critical role in the progression of multiple solid cancers and therapy resistance. The role of LIF/
LIFR in the progression of Type II ECa, on the other hand, is unknown. We investigated the role of LIF/
LIFR signaling in Type II ECa and tested the efficacy of EC359, a novel small-molecule
LIFR inhibitor, against Type II ECa. The analysis of tumor databases has uncovered a correlation between diminished survival rates and increased expression of leukemia inhibitory factor (LIF), suggesting a potential connection between altered LIF expression and unfavorable overall survival in Type II ECa. The results obtained from cell viability and colony formation assays demonstrated a significant decrease in the growth of Type II ECa LIFR knockdown cells in comparison to vector control cells. Furthermore, in both primary and established Type II ECa cells, pharmacological inhibition of the LIF/LIFR axis with EC359 markedly decreased cell viability, long-term cell survival, and invasion, and promoted apoptosis. Additionally, EC359 treatment reduced the activation of pathways driven by LIF/
LIFR, such as AKT, mTOR, and STAT3. Tumor progression was markedly inhibited by EC359 treatment in two different patient-derived xenograft models in vivo and patient-derived organoids ex vivo. Collectively, these results suggest LIFR inhibitor EC359 as a possible new small-molecule therapeutics for the management of Type II ECa.