Department of Translational Hematology Oncology Research, Cleveland Clinic, Cleveland, Ohio.
Research and Development, Pharmaceuticals, Bayer AG, Berlin, Germany.
Cancer Res. 2019 Nov 1;79(21):5640-5651. doi: 10.1158/0008-5472.CAN-19-0859. Epub 2019 Aug 6.
Targeted α-particle-emitting radionuclides have great potential for the treatment of a broad range of cancers at different stages of progression. A platform that accurately measures cancer cellular sensitivity to α-particle irradiation could guide and accelerate clinical translation. Here, we performed high-content profiling of cellular survival following exposure to α-particles emitted from radium-223 (Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. Ra was significantly more potent than sparsely ionizing irradiation, with a median relative biological effectiveness of 10.4 (IQR: 8.4-14.3). Cells that are the most resistant to γ radiation, such as gain-of-function mutant cells, were sensitive to α-particles. Combining these profiling results with genetic features, we identified several somatic copy-number alterations, gene mutations, and the basal expression of gene sets that correlated with radiation survival. Activating mutations in , a frequent event in cancer, decreased sensitivity to Ra. The identification of cellular and genetic determinants of sensitivity to Ra may guide the clinical incorporation of targeted α-particle emitters in the treatment of several cancer types. SIGNIFICANCE: These findings address limitations in the preclinical guidance and prediction of radionuclide tumor sensitivity by identifying intrinsic cellular and genetic determinants of cancer cell survival following exposure to α-particle irradiation..
靶向 α 粒子发射放射性核素在治疗不同进展阶段的广泛癌症方面具有巨大潜力。一个能够准确测量癌症细胞对 α 粒子照射敏感性的平台可以指导和加速临床转化。在这里，我们使用 28 种遗传多样化的人类肿瘤细胞系，对镭-223（Ra）发射的 α 粒子照射后细胞存活进行了高内涵分析。观察到肿瘤细胞之间的细胞敏感性存在显著差异。Ra 比稀疏电离照射更有效，中位数相对生物学效应为 10.4（IQR：8.4-14.3）。对 γ 辐射最具抗性的细胞，如获得功能突变细胞，对 α 粒子敏感。将这些分析结果与遗传特征相结合，我们确定了几个与辐射存活相关的体细胞拷贝数改变、基因突变和基因集的基础表达。癌症中常见的 激活突变降低了对 Ra 的敏感性。确定对 Ra 敏感性的细胞和遗传决定因素可能指导靶向 α 粒子发射体在几种癌症类型的治疗中的临床应用。意义：这些发现通过鉴定暴露于 α 粒子照射后癌细胞存活的内在细胞和遗传决定因素，解决了放射性核素肿瘤敏感性临床指导和预测的局限性。
