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 Chávez-Riveros, Kalarickal V Dileep, Kam Y J Zhang, Xinlei Pan, Ramachandran Murali, Marek Bajda, Ganesh V Raj, Andrew J Brenner, Vijaya Manthati, Manjeet K Rao, Rajeshwar R Tekmal, Hareesh B Nair, Klaus J Nickisch, Ratna K Vadlamudi
Molecular cancer therapeutics 2019 AugLeukemia 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. ©2019 American Association for Cancer Research.
Citation
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 Chávez-Riveros, Kalarickal V Dileep, Kam Y J Zhang, Xinlei Pan, Ramachandran Murali, Marek Bajda, Ganesh V Raj, Andrew J Brenner, Vijaya Manthati, Manjeet K Rao, Rajeshwar R Tekmal, Hareesh B Nair, Klaus J Nickisch, Ratna K Vadlamudi. EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer. Molecular cancer therapeutics. 2019 Aug;18(8):1341-1354
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PMID: 31142661
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