1. The Proteogenomics of Prostate Cancer Radioresistance.
- Author
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Haas R, Frame G, Khan S, Neilsen BK, Hong BH, Yeo CPX, Yamaguchi TN, Ong EHW, Zhao W, Carlin B, Yeo ELL, Tan KM, Bugh YZ, Zhu C, Hugh-White R, Livingstone J, Poon DJJ, Chu PL, Patel Y, Tao S, Ignatchenko V, Kurganovs NJ, Higgins GS, Downes MR, Loblaw A, Vesprini D, Kishan AU, Chua MLK, Kislinger T, Boutros PC, and Liu SK
- Subjects
- Male, Humans, Cell Line, Tumor, DNA Polymerase theta, Genomic Instability, DNA Mismatch Repair, Gene Expression Regulation, Neoplastic, DNA-Directed DNA Polymerase genetics, DNA-Directed DNA Polymerase metabolism, Radiation Dose Hypofractionation, Prostatic Neoplasms radiotherapy, Prostatic Neoplasms genetics, Prostatic Neoplasms metabolism, Prostatic Neoplasms pathology, Radiation Tolerance genetics, Proteogenomics methods
- Abstract
Prostate cancer is frequently treated with radiotherapy. Unfortunately, aggressive radioresistant relapses can arise, and the molecular underpinnings of radioresistance are unknown. Modern clinical radiotherapy is evolving to deliver higher doses of radiation in fewer fractions (hypofractionation). We therefore analyzed genomic, transcriptomic, and proteomic data to characterize prostate cancer radioresistance in cells treated with both conventionally fractionated and hypofractionated radiotherapy. Independent of fractionation schedule, resistance to radiotherapy involved massive genomic instability and abrogation of DNA mismatch repair. Specific prostate cancer driver genes were modulated at the RNA and protein levels, with distinct protein subcellular responses to radiotherapy. Conventional fractionation led to a far more aggressive biomolecular response than hypofractionation. Testing preclinical candidates identified in cell lines, we revealed POLQ (DNA Polymerase Theta) as a radiosensitizer. POLQ-modulated radioresistance in model systems and was predictive of it in large patient cohorts. The molecular response to radiation is highly multimodal and sheds light on prostate cancer lethality., Significance: Radiation is standard of care in prostate cancer. Yet, we have little understanding of its failure. We demonstrate a new paradigm that radioresistance is fractionation specific and identified POLQ as a radioresistance modulator., (©2024 The Authors; Published by the American Association for Cancer Research.)
- Published
- 2024
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