The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.
The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling.
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LIFR抑制剂EC359通过阻断LIF/LIFR致癌信号有效靶向II型子宫内膜癌
DOI：
10.3390/ijms242417426
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发表时间：
2023-12-13
影响因子：
5.6
通讯作者：
Viswanadhapalli, Suryavathi
中科院分区：
文献类型：
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作者：
Spencer, Nicole;Rodriguez Sanchez, Alondra Lee;Gopalam, Rahul;Subbarayalu, Panneerdoss;Medina, Daisy M.;Yang, Xue;Ramirez, Paulina;Randolph, Lois;Aller, Emily Jean;Santhamma, Bindu;Rao, Manjeet K.;Tekmal, Rajeshwar Rao;Nair, Hareesh B.;Kost, Edward R.;Vadlamudi, Ratna K.;Viswanadhapalli, Suryavathi
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 型肿瘤在生物学上比 I 型肿瘤更具侵袭性并且预后更差。目前对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中发挥着关键作用。另一方面，LIF/LIFR 在 II 型 ECa 进展中的作用尚不清楚。我们研究了 LIF/LIFR 信号在 II 型 ECa 中的作用，并测试了 EC359（一种新型小分子 LIFR 抑制剂）针对 II 型 ECa 的功效。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，表明 LIF 表达改变与 II 型 ECa 中不利的总生存期之间存在潜在联系。从细胞活力和集落形成测定中获得的结果表明，与载体对照细胞相比，II 型 ECa LIFR 敲低细胞的生长显着下降。此外，在原代和已建立的 II 型 ECa 细胞中，EC359 对 LIF/LIFR 轴的药理学抑制显着降低细胞活力、长期细胞存活和侵袭，并促进细胞凋亡。此外，EC359 治疗减少了 LIF/LIFR 驱动通路的激活，例如 AKT、mTOR 和 STAT3。在两种不同的体内患者来源的异种移植模型和离体患者来源的类器官中，EC359 治疗显着抑制了肿瘤进展。总的来说，这些结果表明 LIFR 抑制剂 EC359 作为治疗 II 型 ECa 的一种可能的新型小分子疗法。
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.
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DOI：
10.1158/1078-0432.ccr-18-0412
发表时间：
2018-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Soumerai TE;Donoghue MTA;Bandlamudi C;Srinivasan P;Chang MT;Zamarin D;Cadoo KA;Grisham RN;O'Cearbhaill RE;Tew WP;Konner JA;Hensley ML;Makker V;Sabbatini P;Spriggs DR;Troso-Sandoval TA;Charen AS;Friedman C;Gorsky M;Schweber SJ;Middha S;Murali R;Chiang S;Park KJ;Soslow RA;Ladanyi M;Li BT;Mueller J;Weigelt B;Zehir A;Berger MF;Abu-Rustum NR;Aghajanian C;DeLair DF;Solit DB;Taylor BS;Hyman DM
通讯作者：
Hyman DM
白血病抑制因子可以通过PI3K/AKT依赖性MCL-1激活来保护胆管癌细胞免受药物诱导的凋亡。
影响因子：
--
作者：
Morton SD;Cadamuro M;Brivio S;Vismara M;Stecca T;Massani M;Bassi N;Furlanetto A;Joplin RE;Floreani A;Fabris L;Strazzabosco M
通讯作者：
Strazzabosco M
影响因子：
6.8
作者：
Feng, Chang-Zhou;Li, Ning-Zhe;Hu, Xi-Bo;Xie, Yin -Yin;Huang, Qiu-Hua;Zhang, Jianming;Chen, Zhu;Chen, Sai-Juan;Wang, Fudi;Sun, Xiao-Jian
通讯作者：
Sun, Xiao-Jian
影响因子：
15.9
作者：
Liu, Shu-Chen;Tsang, Ngan-Ming;Chang, Yu-Sun
通讯作者：
Chang, Yu-Sun
影响因子：
7
作者：
Tang W;Ramasamy K;Pillai SMA;Santhamma B;Konda S;Pitta Venkata P;Blankenship L;Liu J;Liu Z;Altwegg KA;Ebrahimi B;Pratap UP;Li X;Valente PT;Kost E;Sareddy GR;Vadlamudi RK;Nair HB;Tekmal RR;Viswanadhapalli S
通讯作者：
Viswanadhapalli S