DNA-PK inhibition shows differential radiosensitization in orthotopic GBM PDX models based on DDR pathway deficits.

Autor:	Dragojevic S; Mayo Clinic, Rochester, Minnesota, United States., Smith EJ; Mayo Clinic, Rochester, Minnesota, United States., Regan MS; Brigham and Women's Hospital, Boston, MA, United States., Stopka SA; Brigham and Women's Hospital, Boston, United States., Baquer G; Brigham and Women's Hospital, Boston, MA, United States., Xue Z; Mayo Clinic, Rochester, Minnesota, United States., Zhang W; University of Minnesota, Minneapolis, MN, United States., Connors MA; Mayo Clinic, Rochester, Minnesota, United States., Kloeber JA; Mayo Clinic, Rochester, MN, United States., Hu Z; Mayo Clinic, Rochester, MN, United States., Bakken KK; Mayo Clinic, Rochester, MN, United States., Ott LL; Mayo Clinic, Rochester, Minnesota, United States., Carlson BL; Mayo Clinic, Rochester, United States., Burgenske DM; Mayo Clinic, Rochester, MN, United States., Decker PA; Mayo Clinic, Rochester, United States., Tian S; Mayo Clinic, United States., Gupta SK; Mayo Clinic, Rochester, MN, United States., Laverty DJ; Harvard T.H. Chan School of Public Health, Boston, MA, United States., Eckel-Passow JE; Mayo Clinic, Rochester, MN, United States., Elmquist WF; University of Minnesota, Minneapolis, MN, United States., Agar NYR; Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States., Nagel ZD; Harvard T.H. Chan School of Public Health, Boston, MA, United States., Sarkaria JN; Mayo Clinic, Rochester, MN, United States., Callaghan CM; Mayo Clinic, Rochester, MN, United States.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2024 Oct 23. Date of Electronic Publication: 2024 Oct 23.
DOI:	10.1158/1535-7163.MCT-24-0003
Abstrakt:	Glioblastoma (GBM) remains one of the most therapy-resistant malignancies with frequent local failures despite aggressive surgery, chemotherapy, and ionizing radiation (IR). Small molecule inhibitors of DNA-dependent protein kinase (DNA-PKi's) are potent radiosensitizers currently in clinical trials. Determining which patients may benefit from radiosensitization with DNA-PKi's is critical to avoid unnecessary increased risk of normal tissue toxicity. In this study we used GBM patient derived xenografts (PDXs) in orthotopic murine models to study the relationship between molecular features, pharmacokinetics, and the radiosensitizing potential of the DNA-PKi peposertib. We show that peposertib radiosensitizes established and PDX GBM lines in vitro at 300nM and above, with significant increase in radiosensitization by maintaining post-IR exposure for >12 hours. Radiosensitization by peposertib is mediated by catalytic inhibition of DNA-PK, and knock-down of DNA-PK by short hairpin RNA (shRNA) largely abolished the radiosensitizing effect. Peposertib decreased auto-phosphorylation of DNA-PKcs after IR in a dose-dependent manner with delay in resolution of γH2AX foci at 24 hours. The addition of peposertib to IR significantly increased survival in GBM120 orthotopic xenografts, but not in GBM10. There was no difference in plasma or average tumor concentrations of peposertib in the two cohorts. While the mechanism underpinning this discordant effect in vitro vs. in vivo is not clear, there was an association for greater sensitization in TP53 mutant lines. Transfection of a dominant-negative TP53 mutant in baseline TP53 wildtype GBM lines significantly delayed growth and decreased NHEJ efficiency (but not Homologous Recombination), after peposertib exposure.
Databáze:	MEDLINE
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