EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer

  • Mol Cancer Ther. 2019 Aug;18(8):1341-1354. doi: 10.1158/1535-7163.MCT-18-1258.
Suryavathi Viswanadhapalli  1 ,  Yiliao Luo  1  2 ,  Gangadhara R Sareddy  1  3 ,  Bindu Santhamma  4 ,  Mei Zhou  1  5 ,  Mengxing Li  1  6 ,  Shihong Ma  7 ,  Rajni Sonavane  7 ,  Uday P Pratap  1 ,  Kristin A Altwegg  1 ,  Xiaonan Li  1 ,  Annabel Chang  7 ,  Alejandra Chávez-Riveros  4 ,  Kalarickal V Dileep  8 ,  Kam Y J Zhang  8 ,  Xinlei Pan  9 ,  Ramachandran Murali  9 ,  Marek Bajda  10 ,  Ganesh V Raj  7 ,  Andrew J Brenner  3  11 ,  Vijaya Manthati  4 ,  Manjeet K Rao  3  12 ,  Rajeshwar R Tekmal  1  3 ,  Hareesh B Nair  13 ,  Klaus J Nickisch  4 ,  Ratna K Vadlamudi  14  3
Affiliations
  • 1. Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
  • 2. Department of General Surgery, Xiangya Hospital, Hunan, China.
  • 3. Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
  • 4. Evestra, Inc., San Antonio, Texas.
  • 5. Department of Gastroenterology, Second Xiangya Hospital, Hunan, China.
  • 6. Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, China.
  • 7. UT Southwestern Medical Center, Dallas, Texas.
  • 8. Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
  • 9. Cedars-Sinai Medical Center, Los Angeles, California.
  • 10. Jagiellonian University Medical College, Krakow, Poland.
  • 11. Hematology & Oncology, University of Texas Health San Antonio, San Antonio, Texas.
  • 12. Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
  • 13. Evestra, Inc., San Antonio, Texas. [email protected] [email protected].
  • 14. Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas. [email protected] [email protected].
PMID: 31142661 DOI: 10.1158/1535-7163.MCT-18-1258
Abstract

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. 1337.

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