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Cancer Res. 2019 Aug 6. pii: canres.0859.2019. doi: 10.1158/0008-5472.CAN-19-0859. [Epub ahead of print]

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

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Translational Hematology Oncology Research, Cleveland Clinic.
Research & Development, Bayer AG.
Thorium Conjugate Research, Bayer AS.
Translational Hematology Oncology Research and Radiation Oncology, Cleveland Clinic Lerner College of Medicine


Targeted alpha-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 alpha-particle irradiation could guide and accelerate clinical translation. Herein, we performed high-content profiling of cellular survival following exposure to alpha-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 biologic effectiveness of 10.4 (IQR: 8.4-14.3). Cells that are the most resistant to alpha radiation, such as Nrf2 gain-of-function mutant cells, were sensitive to alpha-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 alpha-particle emitters in the treatment of several cancer types.

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