Cellular and genetic determinants of the sensitivity of cancer to α-particle irradiation

Targeteda-particle-emitting radionuclides have greatpotential 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 highcontent 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-particle emitters in the treatment of several cancer types.