TY - JOUR
T1 - EC359
T2 - A first-in-class small-molecule inhibitor for targeting oncogenic LIFR signaling in triple-negative breast cancer
AU - Viswanadhapalli, Suryavathi
AU - Luo, Yiliao
AU - Sareddy, Gangadhara R.
AU - Santhamma, Bindu
AU - Zhou, Mei
AU - Li, Mengxing
AU - Ma, Shihong
AU - Sonavane, Rajni
AU - Pratap, Uday P.
AU - Altwegg, Kristin A.
AU - Li, Xiaonan
AU - Chang, Annabel
AU - Chavez-Riveros, Alejandra
AU - Dileep, Kalarickal V.
AU - Zhang, Kam Y.J.
AU - Pan, Xinlei
AU - Murali, Ramachandran
AU - Bajda, Marek
AU - Raj, Ganesh V.
AU - Brenner, Andrew J.
AU - Manthati, Vijaya
AU - Rao, Manjeet K.
AU - Tekmal, Rajeshwar R.
AU - Nair, Hareesh B.
AU - Nickisch, Klaus J.
AU - Vadlamudi, Ratna K.
N1 - Funding Information:
G.V. Raj is a founder at EtiraRx and GaudiumRx, reports receiving a commercial research grant from Bayer, has received speakers' bureau honoraria from Bayer, Janssen, Astellas, and Pfizer, is a consultant/advisory board member for Bayer and Janssen. K.J. Nickisch has ownership interest (including stock, patents, etc.) from Evestra. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We thank Jessica Perry (Ob/Gyn UT Health San Antonio) for proofreading of the manuscript. MST studies were performed by 2bind GmbH, Germany. K.V. Dileep thanks Japan Society for the Promotion of Science for a postdoctoral fellowship. This study was supported by the DOD BCRP grant W81XWH-18-1-0016 (to R.K. Vadlamudi and K.J. Nickisch), DOD BCRP grant W81XWH-16-0294 (to R.R. Tekmal), NCI Cancer Center Support Grant P30CA054174-17, Max and Minnie Tomerlin Voelcker Fund (to G.R. Sareddy), and NIH grant 1R01CA179120-01 (to R.K. Vadlamudi and M. Rao).
PY - 2019
Y1 - 2019
N2 - 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.
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.
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U2 - 10.1158/1535-7163.MCT-18-1258
DO - 10.1158/1535-7163.MCT-18-1258
M3 - Article
C2 - 31142661
AN - SCOPUS:85070839852
VL - 18
SP - 1341
EP - 1354
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 8
ER -