Targeting LIF/LIFR signaling in cancer.

靶向癌症中的 LIF / LIFR 信号传导。

• 影响指数: 7.243
• 发表时间: Jul 2022
• 来源期刊: Genes Dis
• DOI: 10.1016/j.gendis.2021.04.003
• PMID: 35685476
• 文章类型: Journal Article
• 作者列表: Viswanadhapalli S,Dileep KV,Zhang KYJ,Nair HB,Vadlamudi RK

关键词: AKT, protein kinase B; HER2, human epidermal growth factor receptor 2; JAK, Janus kinase; LIF; LIF receptor, (LIFR); LIFR; LIFR inhibitor; STAT3; Targeted therapy; breast cancer, (BCa); cancer stem cells, (CSCs); cardiotrophin 1, (CTF1); ciliary neurotrophic factor, (CNTF); colorectal cancer, (CRC); endometrial cancer, (ECa); humanized Anti-LIF antibody, (MSC-1); leukemia inhibitory factor, (LIF); mammalian target of rapamycin, (mTOR); mitogen activated protein kinase, (MAPK); oncostatin M, (OSM); ovarian cancer, (OCa); pancreatic ductal adenocarcinoma, (PDAC); programmed death-ligand 1, (PD-L1); prostate cancer, (PCa); signal transducer and activator of transcription 3, (STAT3); triple negative breast cancer, (TNBC); tumor micro environment, (TME)

Abstract

Leukemia inhibitory factor (LIF), and its receptor (LIFR), are commonly over-expressed in many solid cancers and recent studies have implicated LIF/LIFR axis as a promising clinical target for cancer therapy. LIF/LIFR activate oncogenic signaling pathways including JAK/STAT3 as immediate effectors and MAPK, AKT, mTOR further downstream. LIF/LIFR signaling plays a key role in tumor growth, progression, metastasis, stemness and therapy resistance. Many solid cancers show overexpression of LIF and autocrine stimulation of the LIF/LIFR axis; these are associated with a poorer relapse-free survival. LIF/LIFR signaling also plays a role in modulating multiple immune cell types present in tumor micro environment (TME). Recently, two targeted agents that target LIF (humanized anti-LIF antibody, MSC-1) and LIFR inhibitor (EC359) were under development. Both agents showed effectivity in preclinical models and clinical trials using MSC-1 antibody are in progress. This article reviews the significance of LIF/LIFR pathways and inhibitors that disrupt this process for the treatment of cancer.

摘要

白血病抑制因子(LIF),和它的受体（LIFR），在许多实体癌中通常过表达，最近的研究表明LIF/LIFR轴是癌症治疗的有希望的临床靶标。LIF/LIFR激活致癌信号通路，包括JAK/STAT3作为即时效应子和MAPK，AKT,mTOR进一步下游。LIF/LIFR信号在肿瘤生长中起关键作用，programming,转移,干性和治疗抗性。许多实体癌显示LIF的过表达和LIF/LIFR轴的自分泌刺激;这些与较差的无复发生存率相关。LIF/LIFR信号传导还在调节肿瘤微环境(TME)中存在的多种免疫细胞类型中起作用。最近,两种靶向LIF(人源化抗LIF抗体，MSC-1）和LIFR抑制剂（EC359）正在开发中。两种药剂在临床前模型中显示出有效性,并且使用MSC-1抗体的临床试验正在进行中。本文综述了LIF/LIFR途径和破坏这一过程的抑制剂在癌症治疗中的意义。