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. Kaklamani; Rajeshwar R. Tekmal; Gulzar Ahmed; Ganesh V. Raj; Klaus J. Nickisch; Hareesh B. Nair; Ratna K. Vadlamudi

doi:10.1038/s42003-021-02741-7

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 journal › Article › peer-review

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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 language	English (US)
Article number	1235
Journal	Communications Biology
Volume	4
Issue number	1
DOIs	https://doi.org/10.1038/s42003-021-02741-7
State	Published - Dec 2021

ASJC Scopus subject areas

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

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Li, M., Viswanadhapalli, S., Santhamma, B., Pratap, U. P., Luo, Y., Liu, J., Altwegg, K. A., Tang, W., Liu, Z., Li, X., Ebrahimi, B., Yan, H., Zou, Y., Konda, S., Sareddy, G. R., Xu, Z., Chen, Y., Rao, M. K., Brenner, A. J., ... Vadlamudi, R. K. (2021). LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer. Communications Biology, 4(1), Article 1235. https://doi.org/10.1038/s42003-021-02741-7

Li, M, Viswanadhapalli, S, Santhamma, B, Pratap, UP, Luo, Y, Liu, J, Altwegg, KA, Tang, W, Liu, Z, Li, X, Ebrahimi, B, Yan, H, Zou, Y, Konda, S, Sareddy, GR, Xu, Z, Chen, Y, Rao, MK, Brenner, AJ, Kaklamani, VG, Tekmal, RR, Ahmed, G, Raj, GV, Nickisch, KJ, Nair, HB & Vadlamudi, RK 2021, 'LIFR inhibition enhances the therapeutic efficacy of HDAC inhibitors in triple negative breast cancer', Communications Biology, vol. 4, no. 1, 1235. https://doi.org/10.1038/s42003-021-02741-7

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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.",

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

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month = dec,

doi = "10.1038/s42003-021-02741-7",

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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.

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

Abstract

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