TY - JOUR
T1 - Cellular and genetic determinants of the sensitivity of cancer to α-particle irradiation
AU - Yard, Brian D.
AU - Gopal, Priyanka
AU - Bannik, Kristina
AU - Siemeister, Gerhard
AU - Hagemann, Urs B.
AU - Abazeed, Mohamed E.
N1 - Funding Information:
M.E. Abazeed was supported by NIH KL2TR0002547, NIH R37CA222294, and VeloSano.
Funding Information:
M.E. Abazeed reports receiving a commercial research grant from Bayer AG, other commercial research support from Siemens Healthcare Solutions USA, and honoraria from the speakers bureau of Bayer AG. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-19-0859
DO - 10.1158/0008-5472.CAN-19-0859
M3 - Article
C2 - 31387923
AN - SCOPUS:85074445309
VL - 79
SP - 5640
EP - 5651
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 21
ER -
