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 pre-clinical 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 multi-modal, and sheds light on prostate cancer lethality.
Cancer research communications. 2024 Aug 21 [Epub ahead of print]
Roni Haas, Gavin Frame, Shahbaz Khan, Beth K Neilsen, Boon Hao Hong, Celestia P X Yeo, Takafumi N Yamaguchi, Enya H W Ong, Wenyan Zhao, Benjamin Carlin, Eugenia L L Yeo, Kah M Tan, Yuan Zhe Bugh, Chenghao Zhu, Rupert Hugh-White, Julie Livingstone, Dennis J J Poon, Pek L Chu, Yash Patel, Shu Tao, Vladimir Ignatchenko, Natalie J Kurganovs, Geoff S Higgins, Michelle R Downes, Andrew Loblaw, Danny Vesprini, Amar U Kishan, Melvin L K Chua, Thomas Kislinger, Paul C Boutros, Stanley K Liu
David Geffen School of Medicine at UCLA, Los Angeles, United States., University of Toronto, Canada., Princess Margaret Cancer Centre, Canada., National Cancer Centre Singapore, Singapore., University of California Los Angeles, Los Angeles, California, United States., National Cancer Centre Singapore, Singapore, Singapore., University of California Los Angeles, United States., Duke-NUS Medical School, Singapore., City of Hope, Duarte, CA, United States., University of Toronto, Toronto, Ontario, Canada., Oslo Universitetssykehus, Parkville, VIC, Australia., University of Oxford, Oxford, United Kingdom., Sunnybrook Health Science Centre, Toronto, Canada., Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada., David Geffen School of Medicine at the University of California, Los Angeles, Los Angeles, California, United States., University of Toronto, Toronto, ON, Canada.