Targeted inhibition of leukemia inhibitory factor (LIF)/ LIFR axis for the treatment of Triple Negative Breast Cancer
Technical Report,01 Feb 2019,31 Jan 2020
University of Texas Health Science Center at San Antonio San Antonio United States
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Leukemia inhibitory factor receptor LIFR and its ligand LIF play a critical role in cancer progression, metastasis, stem cell maintenance, and therapy resistance. In this study, we developed a first-in-class inhibitor of LIFR, EC359, which directly interacts with LIFR to effectively block LIFLIFR interactions. EC359 treatment exhibited antiproliferative effects, reduced invasiveness and stemness, and promoted 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 LIFLIFR-driven pathways, including STAT3, mTOR, and AKT. Concomitantly, EC359 was also effective in blocking signaling by other LIFR ligandsCTF1, CNTF, and OSM that interact at LIFLIFR 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.
- Medicine and Medical Research