2. Academic Validation
  3. LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer

  • Commun Biol. 2021 Oct 29;4(1):1235. doi: 10.1038/s42003-021-02741-7.
Mengxing Li  # 1 2,  Suryavathi Viswanadhapalli  # 3,  Bindu Santhamma 4,  Uday P Pratap 1,  Yiliao Luo 1 5,  Junhao Liu 1 6,  Kristin A Altwegg 1 7,  Weiwei Tang 1 8,  Zexuan Liu 1 6,  Xiaonan Li 1,  Behnam Ebrahimi 1,  Hui Yan 9,  Yi Zou 10,  Swapna Konda 4,  Gangadhara R Sareddy 1 7,  Zhenming Xu 7 9,  Yidong Chen 7 10,  Manjeet K Rao 7 10,  Andrew J Brenner 7 11,  Virginia G Kaklamani 7,  Rajeshwar R Tekmal 1 7,  Gulzar Ahmed 4,  Ganesh V Raj 12,  Klaus J Nickisch 4,  Hareesh B Nair 13,  Ratna K Vadlamudi 14 15 16
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 2 Department of Respiratory Medicine, Xiangya Hospital, Central South University, Hunan, 410008, P.R. China.
  • 3 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. viswanadhapa@uthscsa.edu.
  • 4 Evestra, Inc, San Antonio, TX, 78245, USA.
  • 5 Department of General Surgery, Xiangya Hospital, Central South University, Hunan, 410008, P.R. China.
  • 6 Department of Oncology, Xiangya Hospital, Central South University, Hunan, 410008, P.R. China.
  • 7 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 8 Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing University of Chinese Medicine, Nanjing, 210028, China.
  • 9 Department of Microbiology, Immunology and Molecular Genetics, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 10 Greehey Children's Cancer Research Institute, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 11 Department of Hematology & Oncology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA.
  • 12 Departments of Urology and Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, 75390, USA.
  • 13 Evestra, Inc, San Antonio, TX, 78245, USA. hnair@evestra.com.
  • 14 Department of Obstetrics and Gynecology, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
  • 15 Mays Cancer Center, University of Texas Health San Antonio, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
  • 16 Audie L. Murphy Division, South Texas Veterans Health Care System, San Antonio, TX, 78229, USA. vadlamudi@uthscsa.edu.
  • # Contributed equally.
PMID: 34716410 DOI: 10.1038/s42003-021-02741-7
Abstract

Histone deacetylase inhibitors (HDACi) are identified as novel therapeutic agents, however, recent clinical studies suggested that they are marginally effective in treating triple negative breast Cancer (TNBC). Here, we show that first-in-class Leukemia Inhibitory Factor Receptor (LIFRα) inhibitor EC359 could enhance the therapeutic efficacy of HDACi against TNBC. We observed that both targeted knockdown of LIFR with CRISPR or treatment with EC359 enhanced the potency of four different HDACi in reducing cell viability, cell survival, and enhanced Apoptosis compared to monotherapy in TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways activated by HDACi were attenuated by the EC359 + HDACi therapy. Importantly, combination therapy potently inhibited the growth of TNBC patient derived explants, cell derived xenografts and patient-derived xenografts in vivo. Collectively, our results suggest that targeted inhibition of LIFR can enhance the therapeutic efficacy of HDACi in TNBC.

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