Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation

Cancer Research
Brian D YardMohamed E Abazeed

Abstract

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 (223Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. 223Ra 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 Nrf2 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 PIK3CA, a frequent event in cancer, decreased sensitivity to 223Ra. The identification of cellular and genetic determinants of sensitivity to 223Ra may guide the clinical incorporation of targeted α-p...Continue Reading

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Citations

Apr 8, 2020·Cancer Biotherapy & Radiopharmaceuticals·Urs B HagemannAlan S Cuthbertson
Jun 20, 2020·Cancer Biotherapy & Radiopharmaceuticals·Francisco D C Guerra LiberalKevin M Prise
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