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Mol Cancer Ther. 2019 Aug;18(8):1341-1354. doi: 10.1158/1535-7163.MCT-18-1258. Epub 2019 May 29.

EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer.

Author information

1
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
2
Department of General Surgery, Xiangya Hospital, Hunan, China.
3
Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
4
Evestra, Inc., San Antonio, Texas.
5
Department of Gastroenterology, Second Xiangya Hospital, Hunan, China.
6
Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, China.
7
UT Southwestern Medical Center, Dallas, Texas.
8
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
9
Cedars-Sinai Medical Center, Los Angeles, California.
10
Jagiellonian University Medical College, Krakow, Poland.
11
Hematology & Oncology, University of Texas Health San Antonio, San Antonio, Texas.
12
Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
13
Evestra, Inc., San Antonio, Texas. vadlamudi@uthscsa.edu hnair@evestra.com.
14
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas. vadlamudi@uthscsa.edu hnair@evestra.com.

Abstract

Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibits antiproliferative effects, reduces invasiveness and stemness, and promotes apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359 is dependent on LIF and LIFR expression, and treatment with EC359 attenuated the activation of LIF/LIFR-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligands (CTF1, CNTF, and OSM) that interact at LIF/LIFR interface. EC359 significantly reduced tumor progression in TNBC xenografts and patient-derived xenografts (PDX), and reduced proliferation in patient-derived primary TNBC explants. EC359 exhibits distinct pharmacologic advantages, including oral bioavailability, and in vivo stability. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling.See related commentary by Shi et al., p. 1337.

PMID:
31142661
PMCID:
PMC6677593
[Available on 2020-08-01]
DOI:
10.1158/1535-7163.MCT-18-1258

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