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Molecular Cancer Therapeutics
Molecular Cancer Therapeutics

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Small Molecule Therapeutics

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

Suryavathi Viswanadhapalli, Yiliao Luo, Gangadhara R. Sareddy, Bindu Santhamma, Mei Zhou, Mengxing Li, Shihong Ma, Rajni Sonavane, Uday P. Pratap, Kristin A. Altwegg, Xiaonan Li, Annabel Chang, Alejandra Chávez-Riveros, Kalarickal V. Dileep, Kam Y.J. Zhang, Xinlei Pan, Ramachandran Murali, Marek Bajda, Ganesh V. Raj, Andrew J. Brenner, Vijaya Manthati, Manjeet K. Rao, Rajeshwar R. Tekmal, Hareesh B. Nair, Klaus J. Nickisch and Ratna K. Vadlamudi
Suryavathi Viswanadhapalli
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
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Yiliao Luo
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.Department of General Surgery, Xiangya Hospital, Hunan, China.
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Gangadhara R. Sareddy
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
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Bindu Santhamma
Evestra, Inc., San Antonio, Texas.
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Mei Zhou
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.Department of Gastroenterology, Second Xiangya Hospital, Hunan, China.
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Mengxing Li
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, China.
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Shihong Ma
UT Southwestern Medical Center, Dallas, Texas.
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Rajni Sonavane
UT Southwestern Medical Center, Dallas, Texas.
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Uday P. Pratap
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
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Kristin A. Altwegg
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
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Xiaonan Li
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.
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Annabel Chang
UT Southwestern Medical Center, Dallas, Texas.
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  • ORCID record for Annabel Chang
Alejandra Chávez-Riveros
Evestra, Inc., San Antonio, Texas.
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Kalarickal V. Dileep
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
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Kam Y.J. Zhang
Laboratory for Structural Bioinformatics, Center for Biosystems Dynamics Research, RIKEN, Yokohama, Kanagawa, Japan.
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Xinlei Pan
Cedars-Sinai Medical Center, Los Angeles, California.
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Ramachandran Murali
Cedars-Sinai Medical Center, Los Angeles, California.
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Marek Bajda
Jagiellonian University Medical College, Krakow, Poland.
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Ganesh V. Raj
UT Southwestern Medical Center, Dallas, Texas.
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Andrew J. Brenner
Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.Hematology & Oncology, University of Texas Health San Antonio, San Antonio, Texas.
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Vijaya Manthati
Evestra, Inc., San Antonio, Texas.
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Manjeet K. Rao
Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, Texas.
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Rajeshwar R. Tekmal
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
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Hareesh B. Nair
Evestra, Inc., San Antonio, Texas.
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  • For correspondence: vadlamudi@uthscsa.edu hnair@evestra.com
Klaus J. Nickisch
Evestra, Inc., San Antonio, Texas.
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Ratna K. Vadlamudi
Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, Texas.Mays Cancer Center, University of Texas Health San Antonio, San Antonio, Texas.
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  • For correspondence: vadlamudi@uthscsa.edu hnair@evestra.com
DOI: 10.1158/1535-7163.MCT-18-1258 Published August 2019
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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

This article is featured in Highlights of This Issue, p. 1335

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

  • Mol Cancer Ther 2019;18:1341–54

  • Received November 6, 2018.
  • Revision received March 12, 2019.
  • Accepted May 16, 2019.
  • Published first May 29, 2019.
  • ©2019 American Association for Cancer Research.
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Molecular Cancer Therapeutics: 18 (8)
August 2019
Volume 18, Issue 8
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EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer
Suryavathi Viswanadhapalli, Yiliao Luo, Gangadhara R. Sareddy, Bindu Santhamma, Mei Zhou, Mengxing Li, Shihong Ma, Rajni Sonavane, Uday P. Pratap, Kristin A. Altwegg, Xiaonan Li, Annabel Chang, Alejandra Chávez-Riveros, Kalarickal V. Dileep, Kam Y.J. Zhang, Xinlei Pan, Ramachandran Murali, Marek Bajda, Ganesh V. Raj, Andrew J. Brenner, Vijaya Manthati, Manjeet K. Rao, Rajeshwar R. Tekmal, Hareesh B. Nair, Klaus J. Nickisch and Ratna K. Vadlamudi
Mol Cancer Ther August 1 2019 (18) (8) 1341-1354; DOI: 10.1158/1535-7163.MCT-18-1258

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EC359: A First-in-Class Small-Molecule Inhibitor for Targeting Oncogenic LIFR Signaling in Triple-Negative Breast Cancer
Suryavathi Viswanadhapalli, Yiliao Luo, Gangadhara R. Sareddy, Bindu Santhamma, Mei Zhou, Mengxing Li, Shihong Ma, Rajni Sonavane, Uday P. Pratap, Kristin A. Altwegg, Xiaonan Li, Annabel Chang, Alejandra Chávez-Riveros, Kalarickal V. Dileep, Kam Y.J. Zhang, Xinlei Pan, Ramachandran Murali, Marek Bajda, Ganesh V. Raj, Andrew J. Brenner, Vijaya Manthati, Manjeet K. Rao, Rajeshwar R. Tekmal, Hareesh B. Nair, Klaus J. Nickisch and Ratna K. Vadlamudi
Mol Cancer Ther August 1 2019 (18) (8) 1341-1354; DOI: 10.1158/1535-7163.MCT-18-1258
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Molecular Cancer Therapeutics
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