Genetics and Epigenetics Program, The University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX 77030.
Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Proc Natl Acad Sci U S A. 2018 Feb 27;115(9):2198-2203. doi: 10.1073/pnas.1719001115. Epub 2018 Feb 13.
mutations occur in ∼50% of all human tumors, with increased frequency in aggressive cancers that are notoriously difficult to treat. Additionally, p53 missense mutations are remarkably predictive of refractoriness to chemo/radiotherapy in various malignancies. These observations have led to the development of mutant p53-targeting agents that restore p53 function. An important unknown is which p53-mutant tumors will respond to p53 reactivation-based therapies. Here, we found a heterogeneous impact on therapeutic response to p53 restoration, suggesting that it will unlikely be effective as a monotherapy. Through gene expression profiling of -mutant lymphomas, we identified retinoic acid receptor gamma (RARγ) as an actionable target and demonstrated that pharmacological activation of RARγ with a synthetic retinoid sensitizes resistant p53-mutant lymphomas to p53 restoration, while additively improving outcome and survival in inherently sensitive tumors.
突变发生在所有人类肿瘤的约 50%中，在侵袭性癌症中更为常见，这些癌症治疗起来特别困难。此外，p53 错义突变对各种恶性肿瘤的化疗/放疗耐药性具有显著的预测作用。这些观察结果导致了靶向 p53 突变的药物的开发，这些药物可以恢复 p53 的功能。一个重要的未知因素是哪些 p53 突变肿瘤会对基于 p53 再激活的治疗产生反应。在这里，我们发现对 p53 恢复治疗的反应存在异质性，这表明它不太可能作为单一疗法有效。通过对 -突变淋巴瘤的基因表达谱分析，我们确定了维甲酸受体γ (RARγ) 为一个可操作的靶点，并证明用合成维甲酸对 RARγ 的药理学激活使耐药性 p53 突变淋巴瘤对 p53 恢复敏感，同时在固有敏感肿瘤中增加了治疗效果和生存。
