HDAC Inhibition Restores Response to HER2-Targeted Therapy in Breast Cancer via PHLDA1 Induction
Natasha S Clayton1, Edward P Carter1, Abbie E Fearon1
1Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
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.
Insights
Restoring Pleckstrin Homology-Like Domain A member 1 (PHLDA1) expression can overcome resistance to receptor tyrosine kinase inhibitors. Combining an HDAC inhibitor with lapatinib shows synergistic effects in HER2+ breast cancer, potentially prolonging treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Pleckstrin Homology-Like Domain A member 1 (PHLDA1) downregulation causes resistance to targeted therapies in receptor tyrosine kinase-driven cancers.
- Restoring PHLDA1 levels is a potential strategy to overcome this resistance.
- Mitogen-activated protein kinase (MAPK) signaling inhibition is linked to PHLDA1 downregulation.
Purpose of the Study:
- To investigate the role of MAPK signaling and epigenetic modifications in PHLDA1 downregulation.
- To evaluate the efficacy of a class I histone deacetylase (HDAC) inhibitor, 4SC-202, in restoring PHLDA1 expression.
- To assess the synergistic effect of 4SC-202 and lapatinib in lapatinib-resistant HER2+ breast cancer cells.
Main Methods:
- Pharmacological inhibition of MAPK signaling.
- Chromatin immunoprecipitation followed by quantitative PCR (ChIP-qPCR) to analyze epigenetic marks (H3Kme3, H3K27ac) at the PHLDA1 locus.
- Treatment of lapatinib-resistant HER2+ breast cancer cells with 4SC-202 and lapatinib.
Main Results:
- MEK1/2 inhibition, a component of MAPK signaling, leads to PHLDA1 downregulation and decreases epigenetic marks H3Kme3 and H3K27ac at the PHLDA1 locus.
- 4SC-202 treatment restored PHLDA1 expression in lapatinib-resistant HER2+ breast cancer cells.
- Combination therapy of 4SC-202 and lapatinib demonstrated synergistic effects on cell proliferation and colony formation.
Conclusions:
- MAPK signaling inhibition and associated epigenetic changes contribute to PHLDA1 downregulation.
- Class I HDAC inhibition can restore PHLDA1 expression and overcome targeted therapy resistance.
- Co-treatment with 4SC-202 and lapatinib may enhance clinical efficacy in HER2+ breast cancer patients.
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