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Research ArticleBasic Science Investigation
Open Access

Signaling Network Response to α-Particle–Targeted Therapy with the 225Ac-Labeled Minigastrin Analog 225Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors

Yun Qin, Stefan Imobersteg, Stephan Frank, Alain Blanc, Tanja Chiorazzo, Philipp Berger, Roger Schibli, Martin P. Béhé and Michal Grzmil
Journal of Nuclear Medicine June 2023, 64 (6) 873-879; DOI: https://doi.org/10.2967/jnumed.122.264597
Yun Qin
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
2Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland;
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Stefan Imobersteg
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
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Stephan Frank
3Division of Neuropathology, Institute of Pathology, University of Basel, Basel, Switzerland; and
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Alain Blanc
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
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Tanja Chiorazzo
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
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Philipp Berger
4Laboratory of Nanoscale Biology, Paul Scherrer Institute, Villigen, Switzerland
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Roger Schibli
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
2Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, Switzerland;
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Martin P. Béhé
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
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Michal Grzmil
1Center for Radiopharmaceutical Sciences, Paul Scherrer Institute, Villigen, Switzerland;
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Abstract

α-particle emitters have recently been explored as valuable therapeutic radionuclides. Yet, toxicity to healthy organs and cancer radioresistance limit the efficacy of targeted α-particle therapy (TAT). Identification of the radiation-activated mechanisms that drive cancer cell survival provides opportunities to develop new points for therapeutic interference to improve the efficacy and safety of TAT. Methods: Quantitative phosphoproteomics and matching proteomics followed by the bioinformatics analysis were used to identify alterations in the signaling networks in response to TAT with the 225Ac-labeled minigastrin analog 225Ac-PP-F11N (DOTA-(dGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe) in A431 cells, which overexpress cholecystokinin B receptor (CCKBR). Western blot analysis and microscopy verified the activation of the selected signaling pathways. Small-molecule inhibitors were used to validate the potential of the radiosensitizing combinatory treatments both in vitro and in A431/CCKBR tumor–bearing nude mice. Results: TAT-induced alterations were involved in DNA damage response, cell cycle regulation, and signal transduction, as well as RNA transcription and processing, cell morphology, and transport. Western blot analysis and microscopy confirmed increased phosphorylations of the key proteins involved in DNA damage response and carcinogenesis, including p53, p53 binding protein 1 (p53BP1), histone deacetylases (HDACs), and H2AX. Inhibition of HDAC class II, ataxia-telangiectasia mutated (ATM), and p38 kinases by TMP269, AZD1390, and SB202190, respectively, sensitized A431/CCKBR cells to 225Ac-PP-F11N. As compared with the control and monotherapies, the combination of 225Ac-PP-F11N with the HDAC inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) significantly reduced the viability and increased the DNA damage of A431/CCKBR cells, led to the most pronounced tumor growth inhibition, and extended the mean survival of A431/CCKBR xenografted nude mice. Conclusion: Our study revealed the cellular responses to TAT and demonstrated the radiosensitizing potential of HDAC inhibitors to 225Ac-PP-F11N in CCKBR-positive tumors. This proof-of-concept study recommends development of novel radiosensitizing strategies by targeting TAT-activated and survival-promoting signaling pathways.

  • 225Ac
  • phosphoproteomics
  • minigastrin
  • CCKBR
  • radioresistance

Footnotes

  • Published online Feb. 2, 2023.

  • © 2023 by the Society of Nuclear Medicine and Molecular Imaging.

Immediate Open Access: Creative Commons Attribution 4.0 International License (CC BY) allows users to share and adapt with attribution, excluding materials credited to previous publications. License: https://creativecommons.org/licenses/by/4.0/. Details: http://jnm.snmjournals.org/site/misc/permission.xhtml.

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Journal of Nuclear Medicine: 64 (6)
Journal of Nuclear Medicine
Vol. 64, Issue 6
June 1, 2023
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Signaling Network Response to α-Particle–Targeted Therapy with the 225Ac-Labeled Minigastrin Analog 225Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors
Yun Qin, Stefan Imobersteg, Stephan Frank, Alain Blanc, Tanja Chiorazzo, Philipp Berger, Roger Schibli, Martin P. Béhé, Michal Grzmil
Journal of Nuclear Medicine Jun 2023, 64 (6) 873-879; DOI: 10.2967/jnumed.122.264597

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Signaling Network Response to α-Particle–Targeted Therapy with the 225Ac-Labeled Minigastrin Analog 225Ac-PP-F11N Reveals the Radiosensitizing Potential of Histone Deacetylase Inhibitors
Yun Qin, Stefan Imobersteg, Stephan Frank, Alain Blanc, Tanja Chiorazzo, Philipp Berger, Roger Schibli, Martin P. Béhé, Michal Grzmil
Journal of Nuclear Medicine Jun 2023, 64 (6) 873-879; DOI: 10.2967/jnumed.122.264597
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Keywords

  • 225Ac
  • phosphoproteomics
  • minigastrin
  • CCKBR
  • radioresistance
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