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

Mengxing Li, Suryavathi Viswanadhapalli, Bindu Santhamma, Uday P. Pratap, Yiliao Luo, Junhao Liu, Kristin A. Altwegg, Weiwei Tang, Zexuan Liu, Xiaonan Li, Behnam Ebrahimi, Hui Yan, Yi Zou, Swapna Konda, Gangadhara R. Sareddy, Zhenming Xu, Yidong Chen, Manjeet K. Rao, Andrew J. Brenner, Virginia G. KaklamaniRajeshwar R. Tekmal, Gulzar Ahmed, Ganesh V. Raj, Klaus J. Nickisch, Hareesh B. Nair, Ratna K. Vadlamudi

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Article number1235
JournalCommunications Biology
Volume4
Issue number1
DOIs
StatePublished - Dec 2021

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

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