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Supplementary Table 3 from The Proteogenomics of Prostate Cancer Radioresistance

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posted on 2024-09-19, 11:00 authored by 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 Min Tan, Yuan Zhe Bugh, Chenghao Zhu, Rupert Hugh-White, Julie Livingstone, Dennis J.J. Poon, Pek Lim 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

Differential protein abundance of driver cancer genes, following a T-test

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ARTICLE 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. 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.