Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49. https://doi.org/10.3322/caac.21660.

Article  PubMed  Google Scholar 

American Cancer Society. Cancer Statistics Center. 2022. http://cancerstatisticscenter.cancer.org.

Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33. https://doi.org/10.1056/NEJMoa1405095.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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. https://doi.org/10.1056/NEJMoa1014618.

Article  PubMed  PubMed Central  Google Scholar 

Watson PA, Arora VK, Sawyers CL. Emerging mechanisms of resistance to androgen receptor inhibitors in prostate cancer. Nat Rev Cancer. 2015;15:701–11. https://doi.org/10.1038/nrc4016.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sarker D, Reid AH, Yap TA, de Bono JS. Targeting the PI3K/AKT pathway for the treatment of prostate cancer. Clin Cancer Res. 2009;15:4799–805. https://doi.org/10.1158/1078-0432.CCR-08-0125.

Article  CAS  PubMed  Google Scholar 

Carver BS, Chapinski C, Wongvipat J, Hieronymus H, Chen Y, Chandarlapaty S, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19:575–86. https://doi.org/10.1016/j.ccr.2011.04.008.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell. 2011;19:792–804. https://doi.org/10.1016/j.ccr.2011.05.006.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Jamaspishvili T, Berman DM, Ross AE, Scher HI, De Marzo AM, Squire JA, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15:222–34. https://doi.org/10.1038/nrurol.2018.9.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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. https://doi.org/10.1016/j.cell.2015.05.001.

Article  CAS  PubMed  PubMed Central  Google Scholar 

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. https://doi.org/10.1016/j.ccr.2010.05.026.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Rescigno P, Lorente D, Dolling D, Ferraldeschi R, Rodrigues DN, Riisnaes R, et al. Docetaxel treatment in PTEN- and ERG-aberrant metastatic prostate cancers. Eur Urol Oncol. 2018;1:71–7. https://doi.org/10.1016/j.euo.2018.02.006.

Article  PubMed  PubMed Central  Google Scholar 

Ferraldeschi R, Nava Rodrigues D, Riisnaes R, Miranda S, Figueiredo I, Rescigno P, et al. PTEN protein loss and clinical outcome from castration-resistant prostate cancer treated with abiraterone acetate. Eur Urol. 2015;67:795–802. https://doi.org/10.1016/j.eururo.2014.10.027.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sweeney C, Bracarda S, Sternberg CN, Chi KN, Olmos D, Sandhu S, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398:131–42. https://doi.org/10.1016/S0140-6736(21)00580-8.

Article  CAS  PubMed  Google Scholar 

Mohiuddin IS, Kang MH. DNA-PK as an emerging therapeutic target in cancer. Front Oncol. 2019;9:635 https://doi.org/10.3389/fonc.2019.00635.

Article  PubMed  PubMed Central  Google Scholar 

Yue X, Bai C, Xie D, Ma T, Zhou PK. DNA-PKcs: a multi-faceted player in DNA damage response. Front Genet. 2020;11:607428 https://doi.org/10.3389/fgene.2020.607428.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Dylgjeri E, McNair C, Goodwin JF, Raymon HK, McCue PA, Shafi AA, et al. Pleiotropic impact of DNA-PK in cancer and implications for therapeutic strategies. Clin Cancer Res. 2019;25:5623–37. https://doi.org/10.1158/1078-0432.CCR-18-2207.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Goodwin JF, Kothari V, Drake JM, Zhao S, Dylgjeri E, Dean JL, et al. DNA-PKcs-mediated transcriptional regulation drives prostate cancer progression and metastasis. Cancer Cell. 2015;28:97–113. https://doi.org/10.1016/j.ccell.2015.06.004.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Bouchaert P, Guerif S, Debiais C, Irani J, Fromont G. DNA-PKcs expression predicts response to radiotherapy in prostate cancer. Int J Radiat Oncol Biol Phys. 2012;84:1179–85. https://doi.org/10.1016/j.ijrobp.2012.02.014.

Article  CAS  PubMed  Google Scholar 

Goodwin JF, Schiewer MJ, Dean JL, Schrecengost RS, de Leeuw R, Han S, et al. A hormone-DNA repair circuit governs the response to genotoxic insult. Cancer Discov. 2013;3:1254–71. https://doi.org/10.1158/2159-8290.CD-13-0108.

Article  CAS  PubMed  Google Scholar 

Polkinghorn WR, Parker JS, Lee MX, Kass EM, Spratt DE, Iaquinta PJ, et al. Androgen receptor signaling regulates DNA repair in prostate cancers. Cancer Discov. 2013;3:1245–53. https://doi.org/10.1158/2159-8290.CD-13-0172.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Tsuji T, Sapinoso LM, Tran T, Gaffney B, Wong L, Sankar S, et al. CC-115, a dual inhibitor of mTOR kinase and DNA-PK, blocks DNA damage repair pathways and selectively inhibits ATM-deficient cell growth in vitro. Oncotarget. 2017;8:74688–702. https://doi.org/10.18632/oncotarget.20342.

Article  PubMed  PubMed Central  Google Scholar 

Munster P, Mita M, Mahipal A, Nemunaitis J, Massard C, Mikkelsen T, et al. First-in-human phase I study of a dual mTOR kinase and DNA-PK inhibitor (CC-115) in advanced malignancy. Cancer Manag Res. 2019;11:10463–76. https://doi.org/10.2147/CMAR.S208720.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Sweeney CJ, Percent IJ, Babu S, Cultrera JL, Mehlhaff BA, Goodman OB, et al. Phase 1b/2 study of enzalutamide with samotolisib (LY3023414) or placebo in patients with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2022 https://doi.org/10.1158/1078-0432.CCR-21-2326.

Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 2016;34:1402–18. https://doi.org/10.1200/JCO.2015.64.2702.

Article  PubMed  PubMed Central  Google Scholar 

Schonhoft JD, Zhao JL, Jendrisak A, Carbone EA, Barnett ES, Hullings MA, et al. Morphology-predicted large-scale transition number in circulating tumor cells identifies a chromosomal instability biomarker associated with poor outcome in castration-resistant prostate cancer. Cancer Res. 2020;80:4892–903. https://doi.org/10.1158/0008-5472.CAN-20-1216.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Brown LC, Halabi S, Schonhoft JD, Yang Q, Luo J, Nanus DM, et al. Circulating tumor cell chromosomal instability and neuroendocrine phenotype by immunomorphology and poor outcomes in men with mCRPC treated with abiraterone or enzalutamide. Clin Cancer Res. 2021;27:4077–88. https://doi.org/10.1158/1078-0432.CCR-20-3471.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Scher HI, Armstrong AJ, Schonhoft JD, Gill A, Zhao JL, Barnett E, et al. Development and validation of circulating tumour cell enumeration (Epic Sciences) as a prognostic biomarker in men with metastatic castration-resistant prostate cancer. Eur J Cancer. 2021;150:83–94. https://doi.org/10.1016/j.ejca.2021.02.042.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Scher HI, Lu D, Schreiber NA, Louw J, Graf RP, Vargas HA, et al. Association of AR-V7 on circulating tumor cells as a treatment-specific biomarker with outcomes and survival in castration-resistant prostate cancer. JAMA Oncol. 2016;2:1441–9. https://doi.org/10.1001/jamaoncol.2016.1828.

Article  PubMed  PubMed Central  Google Scholar 

Greene SB, Dago AE, Leitz LJ, Wang Y, Lee J, Werner SL, et al. Chromosomal instability estimation based on next generation sequencing and single cell genome wide copy number variation analysis. PLoS ONE. 2016;11:e0165089 https://doi.org/10.1371/journal.pone.0165089.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat Med. 2017;23:703–13. https://doi.org/10.1038/nm.4333.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Annala M, Taavitsainen S, Khalaf DJ, Vandekerkhove G, Beja K, Sipola J, et al. Evolution of castration-resistant prostate cancer in ctDNA during sequential androgen re