TY - JOUR
T1 - LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer
AU - Li, Mengxing
AU - Viswanadhapalli, Suryavathi
AU - Santhamma, Bindu
AU - Pratap, Uday P.
AU - Luo, Yiliao
AU - Liu, Junhao
AU - Altwegg, Kristin A.
AU - Tang, Weiwei
AU - Liu, Zexuan
AU - Li, Xiaonan
AU - Ebrahimi, Behnam
AU - Yan, Hui
AU - Zou, Yi
AU - Konda, Swapna
AU - Sareddy, Gangadhara R.
AU - Xu, Zhenming
AU - Chen, Yidong
AU - Rao, Manjeet K.
AU - Brenner, Andrew J.
AU - Kaklamani, Virginia G.
AU - Tekmal, Rajeshwar R.
AU - Ahmed, Gulzar
AU - Raj, Ganesh V.
AU - Nickisch, Klaus J.
AU - Nair, Hareesh B.
AU - Vadlamudi, Ratna K.
N1 - Funding Information:
We thank Perry Jessica (Ob/Gyn UT Health San Antonio) for proofreading the manuscript. This study was supported by the DOD BCRP grant W81XWH-18-1-0016 (R.K.V.; K.J.N.); and DOD BCRP grant W81XWH-18-1-0021(Z.X.; R.K.V.); NCI Cancer Center Support Grant P30CA054174-17; NIH CTSA UL1TR002645; Voelcker fund young investigator award (G.R.S.) CPRIT Pre-doctoral Fellowship (K.A.A.), UT Foundation/ Shelby Tengg Foundation award 166120/44090 (S.V.), Elsa U. Pardee Foundation grant 166675-44096 (S.V), NIH grant 1R01CA179120-01 (R.K.V.; M.R.), VA Grant I01BX004545 (R.K.V) and CPRIT RP160732 (Y.C.). GCCRI Genome Sequencing Facility is supported by NIH Shared Instrument grant 1S10OD021805-01.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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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U2 - 10.1038/s42003-021-02741-7
DO - 10.1038/s42003-021-02741-7
M3 - Article
C2 - 34716410
AN - SCOPUS:85118460489
SN - 2399-3642
VL - 4
JO - Communications Biology
JF - Communications Biology
IS - 1
M1 - 1235
ER -