EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer
| Autor: | Suryavathi Viswanadhapalli, Marek Bajda, Kam Y. J. Zhang, Ramachandran Murali, Manjeet K. Rao, Klaus J. Nickisch, Mengxing Li, Xiaonan Li, Ganesh V. Raj, Annabel Chang, Ratna K. Vadlamudi, Kalarickal V. Dileep, Shihong Ma, Kristin A. Altwegg, Rajni Sonavane, Vijaya Manthati, Mei Zhou, Yiliao Luo, Hareesh B. Nair, Xinlei Pan, Rajeshwar Rao Tekmal, Uday P. Pratap, Andrew Brenner, Alejandra Chavez-Riveros, Bindu Santhamma, Gangadhara R. Sareddy |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Stem Cell Factor Cancer Research biology Chemistry Leukemia inhibitory factor receptor Article 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology Tumor progression Cell Line Tumor 030220 oncology & carcinogenesis biology.protein Cancer research Signal transduction STAT3 Protein kinase B Leukemia inhibitory factor Triple-negative breast cancer PI3K/AKT/mTOR pathway |
| Zdroj: | Mol Cancer Ther |
| ISSN: | 1538-8514 1535-7163 |
| Popis: | 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 |
| Databáze: | OpenAIRE |
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