Targeted Inhibition of Leukemia Inhibitory Factor (LIF)/ LIFR Axis for the Treatment of Triple Negative Breast Cancer
Abstract
Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression, metastasis, stem cellmaintenance, and therapy resistance. In this study, we developed a first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIF/LIFR interactions. EC359 treatment exhibited antiproliferative effects, reduced invasiveness and stemness, and promoted apoptosis in triple-negative breast cancer (TNBC) cell lines. The activity of EC359is 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. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling that occur in TNBC.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2010
- Accession Number
- AD1100855
Entities
People
- Klaus Nickisch
- Ratna K Vadlamudi
Organizations
- University of Texas Health Science Center at San Antonio