| Title: |
The Proteogenomics of Prostate Cancer Radioresistance |
| Authors: |
Haas, Roni; Frame, Gavin; Khan, Shahbaz; Neilsen, Beth K; Hong, Boon Hao; Yeo, Celestia PX; Yamaguchi, Takafumi N; Ong, Enya HW; Zhao, Wenyan; Carlin, Benjamin; Yeo, Eugenia LL; Tan, Kah Min; Bugh, Yuan Zhe; Zhu, Chenghao; Hugh-White, Rupert; Livingstone, Julie; Poon, Dennis JJ; Chu, Pek Lim; Patel, Yash; Tao, Shu; Ignatchenko, Vladimir; Kurganovs, Natalie J; Higgins, Geoff S; Downes, Michelle R; Loblaw, Andrew; Vesprini, Danny; Kishan, Amar U; Chua, Melvin LK; Kislinger, Thomas; Boutros, Paul C; Liu, Stanley K |
| Source: |
Cancer Research Communications, vol 4, iss 9 |
| Publisher Information: |
eScholarship, University of California |
| Publication Year: |
2024 |
| Collection: |
University of California: eScholarship |
| Subject Terms: |
32 Biomedical and Clinical Sciences (for-2020); 3202 Clinical Sciences (for-2020); 3211 Oncology and Carcinogenesis (for-2020); Aging (rcdc); Urologic Diseases (rcdc); Cancer (rcdc); Genetics (rcdc); Radiation Oncology (rcdc); Prostate Cancer (rcdc); Human Genome (rcdc); Cancer Genomics (rcdc); Precision Medicine (rcdc); Biotechnology (rcdc); Cancer (hrcs-hc); Male (mesh); Humans (mesh); Prostatic Neoplasms (mesh); Radiation Tolerance (mesh); Proteogenomics (mesh); Cell Line; Tumor (mesh); DNA Polymerase theta (mesh); Genomic Instability (mesh); DNA Mismatch Repair (mesh); Gene Expression Regulation; Neoplastic (mesh); DNA-Directed DNA Polymerase (mesh); Radiation Dose Hypofractionation (mesh) |
| Time: |
2463 - 2479 |
| Description: |
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. |
| Document Type: |
article in journal/newspaper |
| File Description: |
application/pdf |
| Language: |
unknown |
| Relation: |
qt7x67g8p6; https://escholarship.org/uc/item/7x67g8p6; https://escholarship.org/content/qt7x67g8p6/qt7x67g8p6.pdf |
| DOI: |
10.1158/2767-9764.crc-24-0292 |
| Availability: |
https://escholarship.org/uc/item/7x67g8p6; https://escholarship.org/content/qt7x67g8p6/qt7x67g8p6.pdf; https://doi.org/10.1158/2767-9764.crc-24-0292 |
| Rights: |
CC-BY |
| Accession Number: |
edsbas.DF57B510 |
| Database: |
BASE |