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

Brian D. Yard, Priyanka Gopal, Kristina Bannik, Gerhard Siemeister, Urs B. Hagemann, Mohamed E. Abazeed*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)5640-5651
Number of pages12
JournalCancer Research
Volume79
Issue number21
DOIs
StatePublished - Nov 1 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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