Targeting LIF/LIFR signaling in cancer

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.

Keywords: 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).