The Proteogenomics of Prostate Cancer Radioresistance - Beyond the Abstract

Radiotherapy with curative intent is a standard of care for localized prostate cancer. Conventionally fractionated radiotherapy involves smaller daily radiation doses spread over several weeks. There has been a shift towards hypofractionated radiation utilizing fewer but higher radiation doses. Our main goal was to explore the molecular underpinnings of hypo vs. conventional fractionation in prostate radiotherapy.


We established radioresistant prostate cancer cells that survived hypofractionated (5 Gy × 10 fractions) or conventional fractionated (2 Gy × 59 fractions) radiotherapy and comprehensively characterized them from a biomolecular perspective. We determined that splitting a radiation dose into more fractions results in a dramatically more aggressive biomolecular phenotype. This phenotype was marked by much higher mutation rates, unique patterns of DNA damage, and strong dysregulation of cancer driver gene expression in an organellar-specific fashion. This is the first demonstration that the nature of radioresistance is dependent upon the fractionation schedule. Our study suggests that hypofractionated radiation not only increases patient convenience and compliance but may be more advantageous from a biological standpoint.

Using the radioresistant cells, we detected genes associated with radioresistance. To verify their clinical relevance, we integrated pre-clinical data with DNA whole-genome and RNA-sequencing of prostate cancer patients. We identified POLQ as a top candidate modulator of radioresistance beyond our model system and as a radiosensitizer in radioresistant cells. The next step will be to validate the effect of POLQ on radioresistant prostate cancer cells in vivo and elucidate the underlying mechanisms associated with our findings.

This study demonstrates the complex proteogenomic response of prostate cancer cells to radiation. This response was partly fractionation dependent, demonstrating the need to suit future translational studies to contemporary fractionation schedules.

Written by: Roni Haas,1,2,3,4 Gavin Frame,5,6 Shahbaz Khan,7 Beth K Neilsen,1,2,3,4,8 Boon Hao Hong,9 Celestia P X Yeo,9 Takafumi N Yamaguchi,1,2,3,4 Enya H W Ong,9 Wenyan Zhao,1,2,3,4 Benjamin Carlin,1,2,3,4 Eugenia L L Yeo,9 Kah Min Tan,9 Yuan Zhe Bugh,1,2,3,4 Chenghao Zhu,1,2,3,4  Rupert Hugh-White,1,2,3,4  Julie Livingstone,1,2,3,4  Dennis J J Poon,9 Pek Lim Chu,9 Yash Patel,1,2,3,4  Shu Tao,1,2,3,4  Vladimir Ignatchenko,7 Natalie J Kurganovs,7 Geoff S Higgins,10 Michelle R Downes,11,12 Andrew Loblaw,6,13 Danny Vesprini,6,13  Amar U Kishan,8 Melvin L K Chua,9,14,15 Thomas Kislinger,5,7 Paul C Boutros,1,2,3,4,5 Stanley K Liu,5,6,13

  1. Department of Human Genetics, University of California, Los Angeles, Los Angeles, California.
  2. Department of Urology, University of California, Los Angeles, Los Angeles, California.
  3. Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, California.
  4. Institute for Precision Health, University of California, Los Angeles, Los Angeles, California.
  5. Department of Medical Biophysics, University of Toronto, Toronto, Canada.
  6. Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Canada.
  7. Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
  8. Department of Radiation Oncology, University of California, Los Angeles, Los Angeles, California.
  9. Division of Medical Sciences, National Cancer Centre Singapore, Singapore, Singapore.
  10. Department of Oncology, University of Oxford, Oxford, United Kingdom.
  11. Division of Anatomic Pathology, Laboratory Medicine and Molecular Diagnostics, Sunnybrook Health Sciences Centre, Toronto, Canada.
  12. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.
  13. Department of Radiation Oncology, University of Toronto, Toronto, Canada.
  14. Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
  15. Duke-NUS Medical School, Singapore, Singapore.
References:

  1. Haas R., Frame G., Khan S. et al. The Proteogenomics of Prostate Cancer Radioresistance. Cancer research communications. 2024. 4(9):2463-2479. doi: 10.1158/2767-9764.CRC-24-0292.

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