HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction

Natasha S Clayton; Edward P Carter; Abbie E Fearon; James A Heward; Lucía Rodríguez Fernández; Lina Boughetane; Edmund H Wilkes; Pedro R Cutillas; Richard P Grose

doi:10.3390/ijms24076228

HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction

Natasha S Clayton, Edward P Carter, Abbie E Fearon, James A Heward, Lucía Rodríguez Fernández, Lina Boughetane, Edmund H Wilkes, Pedro R Cutillas, Richard P Grose

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

3 Citations (SciVal)

Abstract

The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)+ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2+ breast cancer patients.

Original language	English
Article number	6228
Journal	International Journal of Molecular Sciences
Volume	24
Issue number	7
DOIs	https://doi.org/10.3390/ijms24076228
Publication status	Published - 25 Mar 2023

Bibliographical note

Funding Information:
A.F. was funded by a CRUK studentship (C16420/A12995), E.C. by CRUK and Barts Charity grants (A27781, G-002189), and L.F. by a Breast Cancer Now project award (2017NovPR988). This work was also supported by a Cancer Research UK Centre Grant to Barts Cancer Institute (A25137).

Data Availability Statement
Mass spectrometry data used in this study is published on Proteome Xchange with the identifier PXD008859. All other data available upon request.

Keywords

Humans
Female
Lapatinib/pharmacology
Breast Neoplasms/drug therapy
Antineoplastic Agents/pharmacology
Histone Deacetylases
Quinazolines/pharmacology
Drug Resistance, Neoplasm
Receptor, ErbB-2/metabolism
Cell Line, Tumor
Protein Kinase Inhibitors/pharmacology
Transcription Factors/metabolism
TDAG51
lapatinib
breast cancer
drug resistance
HER2
PHLDA1

ASJC Scopus subject areas

Molecular Biology
Spectroscopy
Catalysis
Inorganic Chemistry
Computer Science Applications
Physical and Theoretical Chemistry
Organic Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.3390/ijms24076228Licence: CC BY

Cite this

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title = "HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction",

abstract = "The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)+ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2+ breast cancer patients.",

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author = "Clayton, {Natasha S} and Carter, {Edward P} and Fearon, {Abbie E} and Heward, {James A} and {Rodr{\'i}guez Fern{\'a}ndez}, Luc{\'i}a and Lina Boughetane and Wilkes, {Edmund H} and Cutillas, {Pedro R} and Grose, {Richard P}",

note = "Funding Information: A.F. was funded by a CRUK studentship (C16420/A12995), E.C. by CRUK and Barts Charity grants (A27781, G-002189), and L.F. by a Breast Cancer Now project award (2017NovPR988). This work was also supported by a Cancer Research UK Centre Grant to Barts Cancer Institute (A25137). Data Availability Statement Mass spectrometry data used in this study is published on Proteome Xchange with the identifier PXD008859. All other data available upon request.",

year = "2023",

month = mar,

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doi = "10.3390/ijms24076228",

language = "English",

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T1 - HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction

AU - Clayton, Natasha S

AU - Carter, Edward P

AU - Fearon, Abbie E

AU - Heward, James A

AU - Rodríguez Fernández, Lucía

AU - Boughetane, Lina

AU - Wilkes, Edmund H

AU - Cutillas, Pedro R

AU - Grose, Richard P

N1 - Funding Information: A.F. was funded by a CRUK studentship (C16420/A12995), E.C. by CRUK and Barts Charity grants (A27781, G-002189), and L.F. by a Breast Cancer Now project award (2017NovPR988). This work was also supported by a Cancer Research UK Centre Grant to Barts Cancer Institute (A25137). Data Availability Statement Mass spectrometry data used in this study is published on Proteome Xchange with the identifier PXD008859. All other data available upon request.

PY - 2023/3/25

Y1 - 2023/3/25

N2 - The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)+ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2+ breast cancer patients.

AB - The downregulation of Pleckstrin Homology-Like Domain family A member 1 (PHLDA1) expression mediates resistance to targeted therapies in receptor tyrosine kinase-driven cancers. The restoration and maintenance of PHLDA1 levels in cancer cells thus constitutes a potential strategy to circumvent resistance to inhibitors of receptor tyrosine kinases. Through a pharmacological approach, we identify the inhibition of MAPK signalling as a crucial step in PHLDA1 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the PHLDA1 locus, specifically a decrease in the activatory marks H3Kme3 and H3K27ac. In line with this, we show that treatment with the clinically relevant class I histone deacetylase (HDAC) inhibitor 4SC-202 restores PHLDA1 expression in lapatinib-resistant human epidermal growth factor receptor-2 (HER2)+ breast cancer cells. Critically, we show that when given in combination, 4SC-202 and lapatinib exert synergistic effects on 2D cell proliferation and colony formation capacity. We therefore propose that co-treatment with 4SC-202 may prolong the clinical efficacy of lapatinib in HER2+ breast cancer patients.

KW - Humans

KW - Female

KW - Lapatinib/pharmacology

KW - Breast Neoplasms/drug therapy

KW - Antineoplastic Agents/pharmacology

KW - Histone Deacetylases

KW - Quinazolines/pharmacology

KW - Drug Resistance, Neoplasm

KW - Receptor, ErbB-2/metabolism

KW - Cell Line, Tumor

KW - Protein Kinase Inhibitors/pharmacology

KW - Transcription Factors/metabolism

KW - TDAG51

KW - lapatinib

KW - breast cancer

KW - drug resistance

KW - HER2

KW - PHLDA1

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U2 - 10.3390/ijms24076228

DO - 10.3390/ijms24076228

M3 - Article

C2 - 37047202

SN - 1422-0067

VL - 24

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

IS - 7

M1 - 6228

ER -

HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

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