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

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

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.

Publication types

  • Comment

MeSH terms

  • Cell Line, Tumor
  • Humans
  • Leukemia Inhibitory Factor
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Receptors, OSM-LIF
  • Signal Transduction
  • Triple Negative Breast Neoplasms*

Substances

  • LIFR protein, human
  • Leukemia Inhibitory Factor
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Receptors, OSM-LIF