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Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer

Oncogene volume 44, pages 1746–1760 (2025)Cite this article

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Abstract

In advanced castration resistant prostate cancer (CRPC), mutations in the DNA damage response (DDR) gene ataxia telangiectasia mutated (ATM) are common. While poly(ADP-ribose) polymerase inhibitors are approved in this context, their clinical efficacy remains limited. Thus, there is a compelling need to identify alternative therapeutic avenues for ATM mutant prostate cancer patients. Here, we generated matched ATM-proficient and ATM-deficient CRPC lines to elucidate the impact of ATM loss on DDR in response to DNA damage via irradiation. Through unbiased phosphoproteomic screening, we unveiled that ATM-deficient CRPC lines maintain dependence on downstream ATM targets through activation of ATR and DNA-PKcs kinases. Dual inhibition of ATR and DNA-PKcs effectively inhibited downstream γH2AX foci formation in response to irradiation and radiosensitized ATM-deficient lines to a greater extent than either ATM-proficient controls or single drug treatment. Further, dual inhibition abrogated residual downstream ATM pathway signaling and impaired replication fork dynamics. To circumvent potential toxicity, we leveraged the RUVBL1/2 ATPase inhibitor Compound B, which leads to the degradation of both ATR and DNA-PKcs kinases. Compound B effectively radiosensitized ATM-deficient CRPC in vitro and in vivo, and impacted replication fork dynamics. Overall, dual targeting of both ATR and DNA-PKcs is necessary to block DDR in ATM-deficient CRPC, and Compound B could be utilized as a novel therapy in combination with irradiation in these patients.

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Fig. 1: Generation and validation of ATM-deficient CRPC lines.
Fig. 2: Effective DNA damage repair in ATM-deficient prostate cancer depends on ATR and DNA-PKcs.
Fig. 3: Dual inhibition of ATR and DNA-PKcs is required to impair DNA-Damage repair in ATM-deficient prostate cancer cells.
Fig. 4: Compound B as a novel therapeutic in ATM-deficient prostate cancer.
Fig. 5: Prostate cancer lines demonstrate sensitivity to Compound B compared to the non-transformed prostate epithelial cell line PNT1A.
Fig. 6: Compound B radiosensitizes ATM-deficient 22Rv1 cells in vivo.

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Data availability

The raw phosphoproteomic data in this manuscript can be accessed with accession number # PXD050955 at https://massive.ucsd.edu/ProteoSAFe/index.jsp.

References

  1. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA: A Cancer J Clin. 2023;73:17–48.

    Google Scholar 

  2. Eastham JA, Auffenberg GB, Barocas DA, Chou R, Crispino T, Davis JW, et al. Clinically localized prostate cancer: AUA/ASTRO Guideline, Part I: introduction, risk assessment, staging, and risk-based management. J Urol. 2022;208:10–8.

    Article  PubMed  Google Scholar 

  3. Lowrance W, Dreicer R, Jarrard DF, Scarpato KR, Kim SK, Kirkby E, et al. Updates to advanced prostate cancer: AUA/SUO Guideline (2023). J Urol. 2023;209:1082–90.

    Article  PubMed  Google Scholar 

  4. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N. Engl J Med. 2011;364:1995–2005.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Scher HI, Beer TM, Higano CS, Anand A, Taplin M-E, Efstathiou E, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;375:1437–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tran C, Ouk S, Clegg NJ, Chen Y, Watson PA, Arora V, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. 2009;324:787–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hofstad M, Huang EY, Woods A, Yin Y, Desai NB, Raj GV. Alterations in BRCA2 as determinants of therapy response in prostate cancer. Crit Rev™ Oncogenesis. 2022;27:81–96.

    Article  PubMed  Google Scholar 

  8. Buttigliero C, Tucci M, Bertaglia V, Vignani F, Bironzo P, Di Maio M, et al. Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer. Cancer Treat Rev. 2015;41:884–92.

    Article  CAS  PubMed  Google Scholar 

  9. Mekonnen N, Yang H, Shin YK. Homologous recombination deficiency in ovarian, breast, colorectal, pancreatic, non-small cell lung and prostate cancers, and the mechanisms of resistance to PARP Inhibitors. Front Oncol. 2022;12:880643.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. de Bono J, Mateo J, Fizazi K, Saad F, Shore N, Sandhu S, et al. Olaparib for metastatic castration-resistant prostate cancer. N. Engl J Med. 2020;382:2091–102.

    Article  PubMed  Google Scholar 

  12. Marshall CH, Sokolova AO, McNatty AL, Cheng HH, Eisenberger MA, Bryce AH, et al. Differential response to olaparib treatment among men with metastatic castration-resistant prostate cancer harboring BRCA1 or BRCA2 versus ATM mutations. Eur Urol. 2019;76:452–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stopsack KH. Efficacy of PARP inhibition in metastatic castration-resistant prostate cancer is very different with Non-BRCA DNA repair alterations: reconstructing prespecified endpoints for Cohort B from the Phase 3 PROfound Trial of Olaparib. Eur Urol. 2020;79:442–5.

  14. Anscher MS, Chang E, Gao X, Gong Y, Weinstock C, Bloomquist E, et al. FDA approval summary: rucaparib for the treatment of patients with deleterious BRCA-mutated metastatic castrate-resistant prostate cancer. Oncologist. 2021;26:139–46.

    Article  CAS  PubMed  Google Scholar 

  15. Chi KN, Rathkopf D, Smith MR, Efstathiou E, Attard G, Olmos D, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41:3339–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Abida W, Patnaik A, Campbell D, Shapiro J, Bryce AH, McDermott R, et al. Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration. J Clin Oncol. 2020;38:3763–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fizazi K, Piulats JM, Reaume MN, Ostler P, McDermott R, Gingerich JR, et al. Rucaparib or physician’s choice in metastatic prostate cancer. N. Engl J Med. 2023;388:719–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Yenerall P, Das AK, Wang S, Kollipara RK, Li LS, Villalobos P, et al. RUVBL1/RUVBL2 ATPase activity drives PAQosome maturation, DNA replication and radioresistance in lung cancer. Cell Chem Biol. 2020;27:105–21.e14.

    Article  CAS  PubMed  Google Scholar 

  19. Sanjana NE, Shalem O, Zhang F. Improved vectors and genome-wide libraries for CRISPR screening. Nat Methods. 2014;11:783–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yang CH, Wang Y, Sims M, Cai C, He P, Häcker H, et al. MicroRNA203a suppresses glioma tumorigenesis through an ATM-dependent interferon response pathway. Oncotarget. 2017;8:112980–91.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Cheng LC, Li Z, Graeber TG, Graham NA, Drake JM. Phosphopeptide enrichment coupled with label-free quantitative mass spectrometry to investigate the phosphoproteome in prostate cancer. J Vis Exp. 2018;138:57996.

  22. Nita-Lazar A, Saito-Benz H, White FM. Quantitative phosphoproteomics by mass spectrometry: past, present, and future. Proteomics. 2008;8:4433–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Hebert AS, Prasad S, Belford MW, Bailey DJ, McAlister GC, Abbatiello SE, et al. Comprehensive single-shot proteomics with FAIMS on a hybrid orbitrap mass spectrometer. Anal Chem. 2018;90:9529–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Swearingen KE, Moritz RL. High-field asymmetric waveform ion mobility spectrometry for mass spectrometry-based proteomics. Expert Rev Proteom. 2012;9:505–17.

    Article  CAS  Google Scholar 

  25. Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.

    Article  CAS  PubMed  Google Scholar 

  26. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Blatt EB, Parra K, Neeb A, Buroni L, Bogdan D, Yuan W, et al. Critical role of antioxidant programs in enzalutamide-resistant prostate cancer. Oncogene. 2023;42:2347–59.

  28. Grasso CS, Wu YM, Robinson DR, Cao X, Dhanasekaran SM, Khan AP, et al. The mutational landscape of lethal castration-resistant prostate cancer. Nature. 2012;487:239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Armenia J, Wankowicz SAM, Liu D, Gao J, Kundra R, Reznik E, et al. The long tail of oncogenic drivers in prostate cancer. Nat Genet. 2018;50:645–51.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Stopsack KH, Nandakumar S, Arora K, Nguyen B, Vasselman SE, Nweji B, et al. Differences in prostate cancer genomes by self-reported race: contributions of genetic ancestry, modifiable cancer risk factors, and clinical factors. Clin Cancer Res. 2022;28:318–26.

    Article  CAS  PubMed  Google Scholar 

  31. Stopsack KH, Nandakumar S, Wibmer AG, Haywood S, Weg ES, Barnett ES, et al. Oncogenic genomic alterations, clinical phenotypes, and outcomes in metastatic castration-sensitive prostate cancer. Clin Cancer Res. 2020;26:3230–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Baca SC, Prandi D, Lawrence MS, Mosquera JM, Romanel A, Drier Y, et al. Punctuated evolution of prostate cancer genomes. Cell. 2013;153:666–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, Theurillat JP, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet. 2012;44:685–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Fraser M, Sabelnykova VY, Yamaguchi TN, Heisler LE, Livingstone J, Huang V, et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017;541:359–64.

    Article  CAS  PubMed  Google Scholar 

  35. Kumar A, Coleman I, Morrissey C, Zhang X, True LD, Gulati R, et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 2016;22:369–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Cell-of-Origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell. 2018;173:291–304.e6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chakraborty G, Nandakumar S, Hirani R, Nguyen B, Stopsack KH, Kreitzer C, et al. The impact of PIK3R1 mutations and insulin-PI3K-Glycolytic pathway regulation in prostate cancer. Clin Cancer Res. 2022;28:3603–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Nguyen B, Mota JM, Nandakumar S, Stopsack KH, Weg E, Rathkopf D, et al. Pan-cancer analysis of CDK12 alterations identifies a subset of prostate cancers with distinct genomic and clinical characteristics. Eur Urol. 2020;78:671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hieronymus H, Schultz N, Gopalan A, Carver BS, Chang MT, Xiao Y, et al. Copy number alteration burden predicts prostate cancer relapse. Proc Natl Acad Sci USA. 2014;111:11139–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Ren S, Wei GH, Liu D, Wang L, Hou Y, Zhu S, et al. Whole-genome and transcriptome sequencing of prostate cancer identify new genetic alterations driving disease progression. Eur Urol. 2018;73:322–39.

    Article  CAS  PubMed  Google Scholar 

  42. Weinstein JN, Collisson EA, Mills GB, Shaw KR, Ozenberger BA, Ellrott K, et al. The cancer genome atlas pan-cancer analysis project. Nat Genet. 2013;45:1113–20.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Gao D, Vela I, Sboner A, Iaquinta PJ, Karthaus WR, Gopalan A, et al. Organoid cultures derived from patients with advanced prostate cancer. Cell. 2014;159:176–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Tang F, Xu D, Wang S, Wong CK, Martinez-Fundichely A, Lee CJ, et al. Chromatin profiles classify castration-resistant prostate cancers suggesting therapeutic targets. Science. 2022;376:eabe1505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Abida W, Armenia J, Gopalan A, Brennan R, Walsh M, Barron D, et al. Prospective genomic profiling of prostate cancer across disease states reveals germline and somatic alterations that may affect clinical decision making. JCO Precis Oncol. 2017;1:1–16.

  46. McCabe N, Lord CJ, Tutt AN, Martin N, Smith GC, Ashworth A. BRCA2-deficient CAPAN-1 cells are extremely sensitive to the inhibition of Poly (ADP-Ribose) polymerase: an issue of potency. Cancer Biol Ther. 2005;4:934–6.

    Article  CAS  PubMed  Google Scholar 

  47. Blackford AN, Jackson SP. ATM, ATR, and DNA-PK: the Trinity at the Heart of the DNA damage response. Mol Cell. 2017;66:801–17.

    Article  CAS  PubMed  Google Scholar 

  48. Bass TE, Fleenor DE, Burrell PE, Kastan MB. ATM regulation of the cohesin complex is required for repression of DNA replication and transcription in the vicinity of DNA Double-Strand Breaks. Mol Cancer Res. 2023;21:261–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Kozlov SV, Graham ME, Jakob B, Tobias F, Kijas AW, Tanuji M, et al. Autophosphorylation and ATM activation: additional sites add to the complexity. J Biol Chem. 2011;286:9107–19.

    Article  CAS  PubMed  Google Scholar 

  50. Yap TA, Tan DSP, Terbuch A, Caldwell R, Guo C, Goh BC, et al. First-in-human trial of the oral Ataxia Telangiectasia and RAD3-Related (ATR) inhibitor BAY 1895344 in patients with advanced solid tumors. Cancer Discov. 2021;11:80–91.

    Article  CAS  PubMed  Google Scholar 

  51. Yap TA, O’Carrigan B, Penney MS, Lim JS, Brown JS, de Miguel Luken MJ, et al. Phase I trial of first-in-class ATR Inhibitor M6620 (VX-970) as monotherapy or in combination with carboplatin in patients with advanced solid tumors. J Clin Oncol. 2020;38:3195–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. van Bussel MTJ, Awada A, de Jonge MJA, Mau-Sørensen M, Nielsen D, Schöffski P, et al. A first-in-man phase 1 study of the DNA-dependent protein kinase inhibitor peposertib (formerly M3814) in patients with advanced solid tumours. Br J Cancer. 2021;124:728–35.

    Article  PubMed  Google Scholar 

  53. Zenke FT, Zimmermann A, Sirrenberg C, Dahmen H, Kirkin V, Pehl U, et al. Pharmacologic inhibitor of DNA-PK, M3814, potentiates radiotherapy and regresses human tumors in mouse models. Mol Cancer Therapeutics. 2020;19:1091–101.

    Article  CAS  Google Scholar 

  54. Gorecki L, Andrs M, Rezacova M, Korabecny J. Discovery of ATR kinase inhibitor berzosertib (VX-970, M6620): Clinical candidate for cancer therapy. Pharmacol Ther. 2020;210:107518.

    Article  CAS  PubMed  Google Scholar 

  55. Fokas E, Prevo R, Pollard JR, Reaper PM, Charlton PA, Cornelissen B, et al. Targeting ATR in vivo using the novel inhibitor VE-822 results in selective sensitization of pancreatic tumors to radiation. Cell Death Dis. 2012;3:e441.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Wengner AM, Siemeister G, Lücking U, Lefranc J, Wortmann L, Lienau P, et al. The novel ATR inhibitor BAY 1895344 is efficacious as monotherapy and combined with DNA damage-inducing or repair-compromising therapies in preclinical cancer models. Mol Cancer Ther. 2020;19:26–38.

    Article  CAS  PubMed  Google Scholar 

  57. Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, et al. Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 2006;66:5354–62.

    Article  CAS  PubMed  Google Scholar 

  58. Brown EJ, Baltimore D. Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance. Genes Dev. 2003;17:615–28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Caldecott KW. Causes and consequences of DNA single-strand breaks. Trends Biochem Sci. 2024;49:68–78.

    Article  CAS  PubMed  Google Scholar 

  60. Izumi N, Yamashita A, Iwamatsu A, Kurata R, Nakamura H, Saari B, et al. AAA+ proteins RUVBL1 and RUVBL2 coordinate PIKK activity and function in nonsense-mediated mRNA decay. Sci Signal. 2010;3:ra27.

    Article  PubMed  Google Scholar 

  61. Cussenot O, Berthon P, Berger R, Mowszowicz I, Faille A, Hojman F, et al. Immortalization of human adult normal prostatic epithelial cells by liposomes containing large T-SV40 gene. J Urol. 1991;146:881–6.

    Article  CAS  PubMed  Google Scholar 

  62. Neeb A, Herranz N, Arce-Gallego S, Miranda S, Buroni L, Yuan W, et al. Advanced prostate cancer with ATM Loss: PARP and ATR inhibitors. Eur Urol. 2021;79:200–11.

    Article  CAS  PubMed  Google Scholar 

  63. Tomimatsu N, Mukherjee B, Burma S. Distinct roles of ATR and DNA-PKcs in triggering DNA damage responses in ATM-deficient cells. EMBO Rep. 2009;10:629–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Finzel A, Grybowski A, Strasen J, Cristiano E, Loewer A. Hyperactivation of ATM upon DNA-PKcs inhibition modulates p53 dynamics and cell fate in response to DNA damage. Mol Biol Cell. 2016;27:2360–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Li J, Stern DF. Regulation of CHK2 by DNA-dependent protein kinase. J Biol Chem. 2005;280:12041–50.

    Article  CAS  PubMed  Google Scholar 

  66. Boehme KA, Kulikov R, Blattner C. p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK. Proc Natl Acad Sci USA. 2008;105:7785–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Callén E, Jankovic M, Wong N, Zha S, Chen HT, Difilippantonio S, et al. Essential role for DNA-PKcs in DNA double-strand break repair and apoptosis in ATM-deficient lymphocytes. Mol Cell. 2009;34:285–97.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Schlam‐Babayov S, Bensimon A, Harel M, Geiger T, Aebersold R, Ziv Y, et al. Phosphoproteomics reveals novel modes of function and inter‐relationships among PIKKs in response to genotoxic stress. EMBO J. 2021;40:e104400.

    Article  PubMed  Google Scholar 

  69. Brenner DJ, Curtis RE, Hall EJ, Ron E. Second malignancies in prostate carcinoma patients after radiotherapy compared with surgery. Cancer. 2000;88:398–406.

    Article  CAS  PubMed  Google Scholar 

  70. Kawashiri T, Kobayashi D, Uchida M, Hiromoto S, Inoue M, Ikeda H, et al. Analysis of secondary leukemia and myelodysplastic syndrome after chemotherapy for solid organ tumors using the Food and Drug Administration Adverse Event Reporting System (FAERS). J Pharm Pharm Sci. 2021;24:499–508.

    Article  CAS  PubMed  Google Scholar 

  71. de Almeida LC, Calil FA, Machado-Neto JA, Costa-Lotufo LV. DNA damaging agents and DNA repair: from carcinogenesis to cancer therapy. Cancer Genet. 2021;252-253:6–24.

    Article  PubMed  Google Scholar 

  72. Drake JM, Paull EO, Graham NA, Lee JK, Smith BA, Titz B, et al. Phosphoproteome integration reveals patient-specific networks in prostate cancer. Cell. 2016;166:1041–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank Dr. Ganesh Raj for his guidance and oversight on this project. We would also like to thank Dr. Kathryn O’Donnell for her support and mentorship throughout this project.

Funding

This work was supported by the Department of Defense (DOD) grant W81XWH-21-1-0687 and the National Cancer Institute (NCI) at the National Institutes of Health grant R01CA276058. MH is supported by NCI grant 1F30 CA281268-01. JMD is supported by the Masonic Cancer Center at the University of Minnesota and by the NCI grant R01CA269801. ZES was supported by DOD Prostate Cancer Program for funding grant W81XWH-20-1-0070. The authors would like to acknowledge the outstanding service of the Quantitative Light Microscopy Shared Resource of the Harold C. Simmons Comprehensive Cancer Center, supported in part by an NCI Cancer Center Support Grant, 1P30 CA142543-01. RK is a CPRIT Scholar in Cancer Research of the Cancer Prevention and Research Institute of Texas (CPRIT) and a John L. Roach Scholar in Biomedical Research of the Endowed Scholars Program at UT Southwestern Medical Center.

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Authors and Affiliations

  1. Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA

    Mia Hofstad, Xiaofang Huo & Ralf Kittler

  2. Department of Urology, UT Southwestern Medical Center, Dallas, TX, USA

    Mia Hofstad, Andrea Woods, Karla Parra, Lan Yu & Collin Gilbreath

  3. Department of Pharmacology, University of Minnesota, Minneapolis, MN, USA

    Zoi E. Sychev, Justin M. Drake & Ralf Kittler

  4. Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA

    Alice Mazzagatti & Peter Ly

  5. Department of Radiation Oncology, UT Southwestern Medical Center, Dallas, TX, USA

    Wei-Min Chen & Anthony J. Davis

  6. Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA

    Justin M. Drake

  7. Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, USA

    Ralf Kittler

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  1. Mia Hofstad
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Contributions

MH, LY, and RK conceived the project and designed experiments. MH, AW, XH, WMC, AJD, and CG. performed in vitro experiments and MH analyzed the data. MH and KP performed animal experiments. ZES and JMD assisted with phosphoproteomic data generation and analysis. AM and PL assisted with fiber assays. MH wrote the manuscript with input from all authors.

Corresponding authors

Correspondence to Mia Hofstad or Ralf Kittler.

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Competing interests

JMD has no conflicts relevant to this work. However, he serves as a consultant and Chief Scientific Officer of Astrin Biosciences. The interest related to JMD. has been reviewed and managed by the University of Minnesota in accordance with its Conflict-of-Interest policies. All other authors declare no competing interests.

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All methods in this manuscript were performed in accordance with the relevant guidelines and regulations. All animal work was done under the supervision of the Animal Resource Center (ARC) and approved by the Institutional Animal Care and Use Committee (IACUC) under the protocol number 2021-103107.

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Hofstad, M., Woods, A., Parra, K. et al. Dual inhibition of ATR and DNA-PKcs radiosensitizes ATM-mutant prostate cancer. Oncogene 44, 1746–1760 (2025). https://doi.org/10.1038/s41388-025-03343-x

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