RT Journal Article SR Electronic T1 EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer JF Molecular Cancer Therapeutics JO Mol Cancer Ther FD American Association for Cancer Research SP 1341 OP 1354 DO 10.1158/1535-7163.MCT-18-1258 VO 18 IS 8 A1 Viswanadhapalli, Suryavathi A1 Luo, Yiliao A1 Sareddy, Gangadhara R. A1 Santhamma, Bindu A1 Zhou, Mei A1 Li, Mengxing A1 Ma, Shihong A1 Sonavane, Rajni A1 Pratap, Uday P. A1 Altwegg, Kristin A. A1 Li, Xiaonan A1 Chang, Annabel A1 Chávez-Riveros, Alejandra A1 Dileep, Kalarickal V. A1 Zhang, Kam Y.J. A1 Pan, Xinlei A1 Murali, Ramachandran A1 Bajda, Marek A1 Raj, Ganesh V. A1 Brenner, Andrew J. A1 Manthati, Vijaya A1 Rao, Manjeet K. A1 Tekmal, Rajeshwar R. A1 Nair, Hareesh B. A1 Nickisch, Klaus J. A1 Vadlamudi, Ratna K. YR 2019 UL http://mct.aacrjournals.org/content/18/8/1341.abstract AB 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. 1337This article is featured in Highlights of This Issue, p. 1335