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.

Li, Viswanadhapalli et al utilized multiple in vitro, ex vivo and in vivo models of TNBC to investigate LIFR inhibition. The authors reported that HDAC inhibition in TNBC cells led to an increase of LIFR expression and over activation of the downstream signaling elements (e.g., STAT3, mTOR, AKT), enhancing the aggressive potential of TNBC cells, and an LIFR inhibitor, EC359, synergistically enhanced the efficacy of HADC inhibitors in suppressing TNBC in vitro and in vivo.

Details

Title
LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer
Author
Li, Mengxing 1 ; Suryavathi, Viswanadhapalli 2   VIAFID ORCID Logo  ; Santhamma Bindu 3 ; Pratap, Uday P 2 ; Luo Yiliao 4 ; Liu Junhao 5 ; Altwegg, Kristin A 6 ; Tang, Weiwei 7 ; Liu Zexuan 5 ; Li, Xiaonan 2 ; Ebrahimi Behnam 2 ; Yan, Hui 8 ; Zou, Yi 9 ; Konda Swapna 3 ; Sareddy, Gangadhara R 6   VIAFID ORCID Logo  ; Xu, Zhenming 10 ; Chen, Yidong 11 ; Rao, Manjeet K 11   VIAFID ORCID Logo  ; Brenner, Andrew J 12 ; Kaklamani, Virginia G 13 ; Tekmal, Rajeshwar R 6 ; Gulzar, Ahmed 3 ; Raj, Ganesh V 14   VIAFID ORCID Logo  ; Nickisch, Klaus J 3 ; Nair, Hareesh B 3   VIAFID ORCID Logo  ; Vadlamudi, Ratna K 15   VIAFID ORCID Logo 

 University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Xiangya Hospital, Central South University, Department of Respiratory Medicine, Hunan, P.R. China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
 Evestra, Inc, San Antonio, USA (GRID:grid.433929.6) (ISNI:0000 0004 1792 8171) 
 University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Xiangya Hospital, Central South University, Department of General Surgery, Hunan, P.R. China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Xiangya Hospital, Central South University, Department of Oncology, Hunan, P.R. China (GRID:grid.216417.7) (ISNI:0000 0001 0379 7164) 
 University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health San Antonio, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
 University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); Nanjing University of Chinese Medicine, Department of Obstetrics and Gynecology, Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing, China (GRID:grid.410745.3) (ISNI:0000 0004 1765 1045) 
 University of Texas Health San Antonio, Department of Microbiology, Immunology and Molecular Genetics, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
 University of Texas Health San Antonio, Greehey Children’s Cancer Research Institute, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
10  University of Texas Health San Antonio, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health San Antonio, Department of Microbiology, Immunology and Molecular Genetics, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
11  University of Texas Health San Antonio, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health San Antonio, Greehey Children’s Cancer Research Institute, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
12  University of Texas Health San Antonio, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health San Antonio, Department of Hematology & Oncology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
13  University of Texas Health San Antonio, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880) 
14  University of Texas Southwestern Medical Center at Dallas, Departments of Urology and Pharmacology, Dallas, USA (GRID:grid.267313.2) (ISNI:0000 0000 9482 7121) 
15  University of Texas Health San Antonio, Department of Obstetrics and Gynecology, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); University of Texas Health San Antonio, Mays Cancer Center, San Antonio, USA (GRID:grid.267309.9) (ISNI:0000 0001 0629 5880); South Texas Veterans Health Care System, Audie L. Murphy Division, San Antonio, USA (GRID:grid.280682.6) (ISNI:0000 0004 0420 5695) 
Publication year
2021
Publication date
2021
Publisher
Nature Publishing Group
e-ISSN
23993642
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2588157812
Copyright
© The Author(s) 2021. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.