EC359: A first-in-class small-molecule inhibitor for targeting oncogenic LIFR signaling in triple-negative breast cancer

Suryavathi Viswanadhapalli, Yiliao Luo, Gangadhara R. Sareddy, Bindu Santhamma, Mei Zhou, Mengxing Li, Shihong Ma, Rajni Sonavane, Uday P. Pratap, Kristin A. Altwegg, Xiaonan Li, Annabel Chang, Alejandra Chavez-Riveros, Kalarickal V. Dileep, Kam Y.J. Zhang, Xinlei Pan, Ramachandran Murali, Marek Bajda, Ganesh V. Raj, Andrew J. BrennerVijaya Manthati, Manjeet K. Rao, Rajeshwar R. Tekmal, Hareesh B. Nair, Klaus J. Nickisch, Ratna K. Vadlamudi

Research output: Contribution to journalArticle

4 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1341-1354
Number of pages14
JournalMolecular Cancer Therapeutics
Volume18
Issue number8
DOIs
StatePublished - Jan 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Viswanadhapalli, S., Luo, Y., Sareddy, G. R., Santhamma, B., Zhou, M., Li, M., Ma, S., Sonavane, R., Pratap, U. P., Altwegg, K. A., Li, X., Chang, A., Chavez-Riveros, A., Dileep, K. V., Zhang, K. Y. J., Pan, X., Murali, R., Bajda, M., Raj, G. V., ... Vadlamudi, R. K. (2019). EC359: A first-in-class small-molecule inhibitor for targeting oncogenic LIFR signaling in triple-negative breast cancer. Molecular Cancer Therapeutics, 18(8), 1341-1354. https://doi.org/10.1158/1535-7163.MCT-18-1258