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

Research output: Contribution to journalArticlepeer-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 languageEnglish
Article number6228
JournalInternational Journal of Molecular Sciences
Volume24
Issue number7
DOIs
Publication statusPublished - 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

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