Centre for Tumour Biology, Barts Cancer Institute-a CRUK Centre of Excellence, Queen Mary University of London, London EC1M 6BQ, UK.
Integrative Cell Signalling and Proteomics, Centre for Haemato-Oncology, Barts Cancer Institute, London EC1M 6BQ, UK.
Cell Rep. 2018 Feb 27;22(9):2469-2481. doi: 10.1016/j.celrep.2018.02.028.
Development of resistance causes failure of drugs targeting receptor tyrosine kinase (RTK) networks and represents a critical challenge for precision medicine. Here, we show that PHLDA1 downregulation is critical to acquisition and maintenance of drug resistance in RTK-driven cancer. Using fibroblast growth factor receptor (FGFR) inhibition in endometrial cancer cells, we identify an Akt-driven compensatory mechanism underpinned by downregulation of PHLDA1. We demonstrate broad clinical relevance of our findings, showing that PHLDA1 downregulation also occurs in response to RTK-targeted therapy in breast and renal cancer patients, as well as following trastuzumab treatment in HER2 breast cancer cells. Crucially, knockdown of PHLDA1 alone was sufficient to confer de novo resistance to RTK inhibitors and induction of PHLDA1 expression re-sensitized drug-resistant cancer cells to targeted therapies, identifying PHLDA1 as a biomarker for drug response and highlighting the potential of PHLDA1 reactivation as a means of circumventing drug resistance.
耐药性的发展导致针对受体酪氨酸激酶 (RTK) 网络的药物失效，这是精准医学面临的重大挑战。在这里，我们表明 PHLDA1 的下调对于 RTK 驱动的癌症中获得和维持耐药性至关重要。我们使用成纤维细胞生长因子受体 (FGFR) 抑制在内膜癌细胞中，确定了 Akt 驱动的补偿机制，其基础是 PHLDA1 的下调。我们证明了我们发现的广泛临床相关性，表明 PHLDA1 的下调也会发生在乳腺癌和肾癌患者对 RTK 靶向治疗的反应中，以及曲妥珠单抗治疗 HER2 乳腺癌细胞后。至关重要的是，单独敲低 PHLDA1 足以赋予对 RTK 抑制剂的新生耐药性，并诱导 PHLDA1 表达使耐药性癌细胞重新对靶向治疗敏感，将 PHLDA1 鉴定为药物反应的生物标志物，并强调了重新激活 PHLDA1 作为规避耐药性的一种手段的潜力。
