{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Yard BD"],"funding":["NCATS NIH HHS","NCI NIH HHS","NIH"],"pagination":["5640-5651"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6825554"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["79(21)"],"pubmed_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 (<sup>223</sup>Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. <sup>223</sup>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 <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 <sup>223</sup>Ra. The identification of cellular and genetic determinants of sensitivity to <sup>223</sup>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.<i>See related commentary by Sgouros, p. 5479</i>."],"journal":["Cancer research"],"pubmed_title":["Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation."],"pmcid":["PMC6825554"],"funding_grant_id":["KL2TR0002547","R37 CA222294","R37CA222294","KL2 TR002547"],"pubmed_authors":["Siemeister G","Hagemann UB","Bannik K","Abazeed ME","Yard BD","Gopal P"],"additional_accession":[]},"is_claimable":false,"name":"Cellular and Genetic Determinants of the Sensitivity of Cancer to α-Particle Irradiation.","description":"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 (<sup>223</sup>Ra) using 28 genetically diverse human tumor cell lines. Significant variation in cellular sensitivity across tumor cells was observed. <sup>223</sup>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 <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 <sup>223</sup>Ra. The identification of cellular and genetic determinants of sensitivity to <sup>223</sup>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.<i>See related commentary by Sgouros, p. 5479</i>.","dates":{"release":"2019-01-01T00:00:00Z","publication":"2019 Nov","modification":"2025-04-04T10:29:52.86Z","creation":"2025-04-04T10:29:52.86Z"},"accession":"S-EPMC6825554","cross_references":{"pubmed":["31387923"],"doi":["10.1158/0008-5472.CAN-19-0859","10.1158/0008-5472.can-19-0859"]}}