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.
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 -