Abstract
The molecular mechanisms underlying sensitivity and resistance to radiotherapy is an area of active investigation and discovery as its clinical applications have the potential to improve cancer patients’ outcomes. In addition to the traditional pathways of radiation biology, our knowledge now includes molecular pathways of radiation sensitivity and resistance which have provided insights into potential targets for enhancing radiotherapy efficacy. Sensitivity to radiotherapy is influenced by the intricate interplay of various molecular mechanisms involved in DNA damage repair, apoptosis, cellular senescence, and epigenetics. Translationally, there have been several successful applications of this new knowledge into the clinic, such as biomarkers for improved response to chemo-radiation. New therapies to modify radiation response, such as the poly (ADP-ribose) polymerase (PARP) inhibitors, derived from research on DNA repair pathways leading to radiotherapy resistance, are being used clinically. In addition, p53-mediated pathways are critical for DNA damage related apoptosis, cellular senescence, and cell cycle arrest. As the understanding of genetic markers, molecular profiling, molecular imaging, and functional assays improve, these advances once translated clinically, will help propel modern radiation therapy towards more precise and individualized practices.
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References
Baskar R, Lee KA, Yeo R, Yeoh KW (2012) Cancer and radiation therapy: current advances and future directions. Int J Med Sci 9(3):193–199. https://doi.org/10.7150/ijms.3635Epub 2012 Feb 27. PMID: 22408567; PMCID: PMC3298009
Arenz A, Ziemann F, Mayer C et al (2014) Increased radiosensitivity of HPV-positive head and neck cancer cell lines due to cell cycle dysregulation and induction of apoptosis. Strahlenther Onkol 190:839–846. https://doi.org/10.1007/s00066-014-0605-5
Hall E, Giaccia A (2018) Radiobiology for Radiologist. Lippincott Williams & Wilkins, Philadelphia
Sinclair WK (1968) Cyclic X-ray responses in mammalian cells in vitro. Radiat Res. 2012;178(2):AV112-AV124. https://doi.org/10.1667/rrav09.1
Bouwman P, Jonkers J (2012) The effects of deregulated DNA damage signaling on cancer chemotherapy response and resistance. Nat Rev Cancer 12(9):587–598. https://doi.org/10.1038/nrc3342
Vispé S, Cazaux C, Lesca C, Defais M Overexpression of Rad51 protein stimulates homologous recombination and increases resistance of mammalian cells to ionizing radiation, Nucleic Acids Research, Volume 26, Issue 12, 1 June 1998, Pages 2859–2864, https://doi.org/10.1093/nar/26.12.2859
Vousden KH, Prives C (2009) Blinded by the light: the growing complexity of p53. Cell 137(3):413–431. https://doi.org/10.1016/j.cell.2009.04.037
Rodier F, Campisi J (2011) Four faces of cellular senescence. J Cell Biol 192(4):547–556. https://doi.org/10.1083/jcb.201009094
Bieging KT, Mello SS, Attardi LD (2014) Unravelling mechanisms of p53-mediated tumour suppression. Nat Rev Cancer 14(5):359–370. https://doi.org/10.1038/nrc3711
Pawlik TM, Keyomarsi K (2004) Role of cell cycle in mediating sensitivity to radiotherapy. Int J Radiat Oncol Biol Phys 59(4):928–942. https://doi.org/10.1016/j.ijrobp.2004.03.005
Kim NH, Kim HS, Li XY et al (2011) A p53/miRNA-34 axis regulates Snail1-dependent cancer cell epithelial-mesenchymal transition. J Cell Biol 195(3):417–433. https://doi.org/10.1083/jcb.201103097
Rivlin N, Brosh R, Oren M, Rotter V (2011) Mutations in the p53 tumor suppressor gene: important milestones at the various steps of Tumorigenesis. Genes Cancer 2(4):466–474. https://doi.org/10.1177/1947601911408889PMID: 21779514; PMCID: PMC3135636
Zhang L, Lu Q, Chang C (2020) Epigenetics in Health and Disease. Adv Exp Med Biol 1253:3–55. https://doi.org/10.1007/978-981-15-3449-2_1
Hegi ME, Liu L, Herman JG et al (2008) Correlation of O6-methylguanine methyltransferase (MGMT) promoter methylation with clinical outcomes in glioblastoma and clinical strategies to modulate MGMT activity. J Clin Oncol 26(25):4189–4199. https://doi.org/10.1200/JCO.2007.11.5964
Hegi ME, Diserens AC, Gorlia T et al (2005) MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med 352:997–1003
Morrison C, Weterings E, Mahadevan D, Sanan A, Weinand M, Stea B (2021) Expression levels of RAD51 inversely correlate with survival of Glioblastoma patients. Cancers 13(21):5358. https://doi.org/10.3390/cancers13215358
Lickliter JD, Ruben J, Kichenadasse G, Jennens R, Gzell C, Mason RP, Zhou H, Becker J, Unger E, Stea B (2023) Dodecafluoropentane Emulsion as a Radiosensitizer in Glioblastoma Multiforme. Cancer Res Commun 3(8):1607–1614. https://doi.org/10.1158/2767-9764.CRC-22-0433PMID: 37609003; PMCID: PMC10441549
Liu YP, Zheng CC, Huang YN, He ML, Xu WW, Li B (2020) Molecular mechanisms of chemo- and radiotherapy resistance and the potential implications for cancer treatment. Med Comm 2021;2(3):315–340. https://doi.org/10.1002/mco2.55
Huang RX, Zhou PK (2020) DNA damage response signaling pathways and targets for radiotherapy sensitization in cancer. Signal Transduct Target Ther 5(1):60. https://doi.org/10.1038/s41392-020-0150-x. Published 2020 May 1
Ang MK, Patel MR, Yin XY et al (2011) High XRCC1 protein expression is associated with poorer survival in patients with head and neck squamous cell carcinoma. Clin Cancer Res 17(20):6542–6552. https://doi.org/10.1158/1078-0432.CCR-10-1604
Terrazzino S, La Mattina P, Masini L et al (2012) Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery. Radiother Oncol 103(2):199–205. https://doi.org/10.1016/j.radonc.2011.12.002
Osti MF, Nicosia L, Agolli L et al (2017) Potential role of single nucleotide polymorphisms of XRCC1, XRCC3, and RAD51 in Predicting Acute toxicity in rectal Cancer patients treated with preoperative Radiochemotherapy. Am J Clin Oncol 40(6):535–542. https://doi.org/10.1097/COC.0000000000000182
Sak SC, Harnden P, Johnston CF, Paul AB, Kiltie AE (2005) APE1 and XRCC1 protein expression levels predict cancer-specific survival following radical radiotherapy in bladder cancer. Clin Cancer Res 11(17):6205–6211. https://doi.org/10.1158/1078-0432.CCR-05-0045
Pedersen H, Adanma Obara E, Elbæk KJ, Vitting-Serup K, Hamerlik P, Replication Protein A (RPA) Mediates Radio-Resistance of Glioblastoma Cancer Stem-Like Cells (eds) (2020) Int J Mol Sci. 21(5):1588. Published 2020 Feb 26. https://doi.org/10.3390/ijms21051588
VanderVere-Carozza PS, Gavande NS, Jalal SI et al (2022) Vivo targeting replication protein A for Cancer Therapy. Front Oncol 12:826655 Published 2022 Feb 18. https://doi.org/10.3389/fonc.2022.826655
Hunia J, Gawalski K, Szredzka A, Suskiewicz MJ, Nowis D (2022) The potential of PARP inhibitors in targeted cancer therapy and immunotherapy. Front Mol Biosci 9:1073797 Published 2022 Dec 1. https://doi.org/10.3389/fmolb.2022.1073797
Ryu H, Kim HJ, Song JY et al (2019) A small compound KJ-28d enhances the sensitivity of Non-small Cell Lung Cancer to Radio- and chemotherapy. Int J Mol Sci 20(23):6026 Published 2019 Nov 29. https://doi.org/10.3390/ijms20236026
Suwa T, Kobayashi M, Nam JM, Harada H (2021) Tumor microenvironment and radioresistance. Exp Mol Med 53(6):1029–1035. https://doi.org/10.1038/s12276-021-00640-9
Chu TY, Yang JT, Huang TH, Liu HW (2014) Crosstalk with cancer-associated fibroblasts increases the growth and radiation survival of cervical cancer cells. Radiat Res. 181(5):540–7. https://doi.org/10.1667/RR13583.1. Epub 2014 May 1. PMID: 24785588
Chen Z, Dominello MM, Joiner MC, Burmeister JW (2023) Proton versus photon radiation therapy: A clinical review. Front Oncol. 13:1133909. Published 2023 Mar 29. https://doi.org/10.3389/fonc.2023.1133909
Sartor O, de Bono J, Chi KN et al (2021) Lutetium-177-PSMA-617 for metastatic castration-resistant prostate Cancer. N Engl J Med 385(12):1091–1103. https://doi.org/10.1056/NEJMoa2107322
English KK, Knox S, Graves SA, Kiess AP (2022) Basics of physics and Radiobiology for Radiopharmaceutical therapies. Pract Radiat Oncol 12(4):289–293. https://doi.org/10.1016/j.prro.2022.04.004
Evaluation of 177 Lu-DOTA-EB-FAPI in patients with metastatic Radioactive Iodine refractory thyroid Cancer. ClinicalTrials.gov Identifier: NCT05410821
Borghini A, Vecoli C, Labate L, Panetta D, Andreassi MG, Gizzi LA (2022) FLASH ultra-high dose rates in radiotherapy: preclinical and radiobiological evidence. Int J Radiat Biol 98(2):127–135. https://doi.org/10.1080/09553002.2022.2009143
Favaudon V, Caplier L, Monceau V et al (2014) Ultrahigh dose-rate FLASH irradiation increases the differential response between normal and tumor tissue in mice [published correction appears in Sci Transl Med. 2019;11(523)]. Sci Transl Med 6(245):245ra93. https://doi.org/10.1126/scitranslmed.3008973
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Xing, J.L., Stea, B. Molecular mechanisms of sensitivity and resistance to radiotherapy. Clin Exp Metastasis (2024). https://doi.org/10.1007/s10585-023-10260-4
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DOI: https://doi.org/10.1007/s10585-023-10260-4