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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article (Academic Journal) › peer-review

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).

Publisher Copyright:
© 2023 by the authors.

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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.",

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). Publisher Copyright: {\textcopyright} 2023 by the authors.",

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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). Publisher Copyright: © 2023 by the authors.

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.

UR - https://europepmc.org/articles/PMC10094256

U2 - 10.3390/ijms24076228

DO - 10.3390/ijms24076228

M3 - Article (Academic Journal)

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SN - 1661-6596

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

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