biostudies-literatureYard BDNCATS NIH HHSNCI NIH HHSNIH5640-5651https://www.ebi.ac.uk/biostudies/studies/S-EPMC6825554biostudies-literatureUnknown79(21)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 <i>Nrf2</i> 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 <i>PIK3CA</i>, 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. 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.<i>See related commentary by Sgouros, p. 5479</i>.Cancer researchCellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation.PMC6825554KL2TR0002547R37 CA222294R37CA222294KL2 TR002547Siemeister GHagemann UBBannik KAbazeed MEYard BDGopal PfalseCellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation.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 <i>Nrf2</i> 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 <i>PIK3CA</i>, 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. 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.<i>See related commentary by Sgouros, p. 5479</i>.2019-01-01T00:00:00Z2019 Nov2025-04-04T10:29:52.86Z2025-04-04T10:29:52.86ZS-EPMC68255543138792310.1158/0008-5472.CAN-19-085910.1158/0008-5472.can-19-0859