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