The LIFR Inhibitor EC359 Effectively Targets Type II Endometrial Cancer by Blocking LIF/LIFR Oncogenic Signaling
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Published:2023-12-13
Issue:24
Volume:24
Page:17426
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ISSN:1422-0067
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Container-title:International Journal of Molecular Sciences
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language:en
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Short-container-title:IJMS
Author:
Spencer Nicole1, Rodriguez Sanchez Alondra Lee1, Gopalam Rahul1, Subbarayalu Panneerdoss2, Medina Daisy M.2ORCID, Yang Xue1ORCID, Ramirez Paulina1, Randolph Lois1, Aller Emily Jean1, Santhamma Bindu3, Rao Manjeet K.2, Tekmal Rajeshwar Rao1, Nair Hareesh B.3, Kost Edward R.1, Vadlamudi Ratna K.145ORCID, Viswanadhapalli Suryavathi14ORCID
Affiliation:
1. Division of Reproductive Research, Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX 78229, USA 2. Department of Cell Systems & Anatomy, Greehey Children’s Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX 78229, USA 3. Evestra, Inc., San Antonio, TX 78245, USA 4. Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX 78229, USA 5. Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX 78229, USA
Abstract
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.
Subject
Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis
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