Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London EC1M 6BQ, UK.
Int J Mol Sci. 2023 Mar 25;24(7):6228. doi: 10.3390/ijms24076228.
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 downregulation. Further ChIP-qPCR analysis revealed that MEK1/2 inhibition produces significant epigenetic changes at the 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.
PHLDA1 表达下调介导受体酪氨酸激酶驱动的癌症对靶向治疗的耐药性。因此，恢复和维持癌细胞中的 PHLDA1 水平构成了规避受体酪氨酸激酶抑制剂耐药性的潜在策略。通过药理学方法，我们确定 MAPK 信号的抑制是下调的关键步骤。进一步的 ChIP-qPCR 分析显示，MEK1/2 抑制在 基因座产生显著的表观遗传变化，特别是激活标记 H3Kme3 和 H3K27ac 的减少。与此一致，我们表明，用临床相关的 I 类组蛋白去乙酰化酶（HDAC）抑制剂 4SC-202 处理可恢复拉帕替尼耐药的人表皮生长因子受体-2（HER2）乳腺癌细胞中的 PHLDA1 表达。至关重要的是，我们表明，当联合使用时，4SC-202 和拉帕替尼对 2D 细胞增殖和集落形成能力具有协同作用。因此，我们提出联合使用 4SC-202 可能延长曲妥珠单抗在 HER2 乳腺癌患者中的临床疗效。
