Opportunities and challenges of radiotherapy for treating cancer

Nature Reviews Clinical Oncology

Volumn 12, Issue 9, 2015, Pages 527-540

  Schaue, Dörthe ^a   Mcbride, William H ^a  

^a UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ATM PROTEIN; BRCA1 PROTEIN; BRCA2 PROTEIN; CHEMOKINE RECEPTOR CXCR4; CYCLIN DEPENDENT KINASE 1; DNA TOPOISOMERASE INHIBITOR; EPIDERMAL GROWTH FACTOR RECEPTOR; FLUOROURACIL; GAMMA SECRETASE INHIBITOR; GEMCITABINE; HISTONE DEACETYLASE INHIBITOR; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INTERLEUKIN 1; NICOTINAMIDE ADENINE DINUCLEOTIDE ADENOSINE DIPHOSPHATE RIBOSYLTRANSFERASE 1; NOTCH RECEPTOR; ROMIDEPSIN; SONIC HEDGEHOG PROTEIN; STROMAL CELL DERIVED FACTOR 1; TUMOR NECROSIS FACTOR ALPHA; VORINOSTAT; WNT PROTEIN;

ADAPTIVE IMMUNITY; ANTIGEN PRESENTING CELL; CANCER RADIOTHERAPY; CELL CYCLE ARREST; CELL CYCLE PROGRESSION; CELL CYCLE REGULATION; CELL RENEWAL; CHROMATIN CONDENSATION; CHROMATIN STRUCTURE; CUTANEOUS T CELL LYMPHOMA; DENDRITIC CELL; DNA END JOINING REPAIR; DNA METHYLATION; DNA MODIFICATION; DNA REPAIR; DNA REPLICATION; DOWN REGULATION; GENE EXPRESSION PROFILING; GENE MUTATION; HOMOLOGOUS RECOMBINATION; HUMAN; IMMUNOSTIMULATION; INTENSITY MODULATED RADIATION THERAPY; IONIZING RADIATION; NEOPLASM; OXIDATION REDUCTION STATE; PRIORITY JOURNAL; PROTEIN PHOSPHORYLATION; RADIATION DOSE; RADIOBIOLOGY; RADIOSENSITIVITY; RADIOSENSITIZATION; REGULATORY T LYMPHOCYTE; REOXYGENATION; REVIEW; SIGNAL TRANSDUCTION; STEREOTACTIC BODY RADIATION THERAPY; SYSTEMATIC REVIEW; TRANSCRIPTION REGULATION; TUMOR MICROENVIRONMENT; NEOPLASMS; RADIATION DOSE FRACTIONATION; TRENDS;

DOSE FRACTIONATION; HUMANS; NEOPLASMS; RADIOTHERAPY;

EID: 84940459327     PISSN: 17594774     EISSN: 17594782     Source Type: Journal    
DOI: 10.1038/nrclinonc.2015.120     Document Type: Review

References (228)

1. Thariat J., Hannoun-Levi J. M., Sun Myint A., Vuong T., & Gerard J. P. Past, present, and future of radiotherapy for the benefit of patients. Nat. Rev. Clin. Oncol. 10, 52-60 (2013
2. Loeffler J. S., & Durante M. Charged particle therapy-optimization, challenges and future directions. Nat. Rev. Clin. Oncol. 10, 411-424 (2013
3. Lo S. S., et al. Stereotactic body radiation therapy: a novel treatment modality. Nat. Rev. Clin. Oncol. 7, 44-54 (2010
4. Withers H. R. The 4Rs of radiotherapy in Advances in Radiation Biology Vol. 5 (eds Lett J. T., & Alder H.) 241-249 (New York: Academic Press, 1975
5. Steel G. G., McMillan T. J., & Peacock J. H. The 5Rs of radiobiology. Int. J. Radiat. Biol. 56, 1045-1048 (1989
6. Good J. S., & Harrington K. J. The hallmarks of cancer and the radiation oncologist: updating the 5Rs of radiobiology. Clin. Oncol. (R. Coll. Radiol.) 25, 569-577 (2013
7. Helleday T., Petermann E., Lundin C., Hodgson B., & Sharma R. A. DNA repair pathways as targets for cancer therapy. Nat. Rev. Cancer 8, 193-204 (2008
8. Chinnaiyan P., Allen G. W., & Harari P. M. Radiation and new molecular agents, part II: targeting HDAC, HSP90, IGF-1R, PI3K, and Ras. Semin. Radiat. Oncol. 16, 59-64 (2006
9. Rizvi N. A., et al. Cancer immunology. Mutational landscape determines sensitivity to PD 1 blockade in non-small cell lung cancer. Science 348, 124-128 (2015
10. Fuks Z., & Kolesnick R. Engaging the vascular component of the tumor response. Cancer Cell 8, 89-91 (2005
11. Masterson L., et al. De-escalation treatment protocols for human papillomavirus-associated oropharyngeal squamous cell carcinoma. Cochrane Database of Systematic Reviews, Issue 2. Art. No.: CD010271 http://dx.doi.org/10.1002/14651858.CD010271.pub2 (2014
12. Lomax M. E., Folkes L. K., & ONeill P. Biological consequences of radiation-induced DNA damage: relevance to radiotherapy. Clin. Oncol. (R. Coll. Radiol.) 25, 578-585 (2013
13. Kastan M. B., Onyekwere O., Sidransky D., Vogelstein B., & Craig R. W. Participation of p53 protein in the cellular response to DNA damage. Cancer Res. 51, 6304-6311 (1991
14. Rogakou E. P., Pilch D. R., Orr A. H., Ivanova V. S., & Bonner W. M. DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J. Biol. Chem. 273, 5858-5868 (1998
15. Jackson S. P., & Bartek J. The DNA-damage response in human biology and disease. Nature 461, 1071-1078 (2009
16. Wang X., et al. Chk1-mediated phosphorylation of FANCE is required for the Fanconi anemia/BRCA pathway. Mol. Cell Biol. 27, 3098-3108 (2007
17. Bekker-Jensen S., & Mailand N. Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair (Amst.) 9, 1219-1228 (2010
18. Lieber M. R. NHEJ and its backup pathways in chromosomal translocations. Nat. Struct. Mol. Biol. 17, 393-395 (2010
19. Lieber M. R., & Wilson T. E. SnapShot: nonhomologous DNA end joining (NHEJ). Cell 142, 496-496.e1 (2010
20. San Filippo J., Sung P., & Klein H. Mechanism of eukaryotic homologous recombination. Annu. Rev. Biochem. 77, 229-257 (2008
21. Onn I., Heidinger-Pauli J. M., Guacci V., Unal E., & Koshland D. E. Sister chromatid cohesion: a simple concept with a complex reality. Annu. Rev. Cell Dev. Biol. 24, 105-129 (2008
22. Maréchal A., & Zou L. RPA-coated single-stranded DNA as a platform for post-translational modifications in the DNA damage response. Cell Res. 25, 9-23 (2014
23. Moore S., Stanley F. K., & Goodarzi A. A. The repair of environmentally relevant DNA double strand breaks caused by high linear energy transfer irradiation-no simple task. DNA Repair (Amst.) 17, 64-73 (2014
24. Takahashi A., et al. Nonhomologous end-joining repair plays a more important role than homologous recombination repair in defining radiosensitivity after exposure to high-LET radiation. Radiat. Res. 182, 338-344 (2014
25. Averbeck N. B., et al. DNA end resection is needed for the repair of complex lesions in G1 phase human cells. Cell Cycle 13, 2509-2516 (2014
26. Durante M. New challenges in high-energy particle radiobiology. Br. J. Radiol. 87, 20130626 (2014
27. Nakajima N. I., et al. Pre-exposure to ionizing radiation stimulates DNA double strand break end resection, promoting the use of homologous recombination repair. PLoS ONE 10, e0122582 (2015
28. Shrivastav M., De Haro L. P., & Nickoloff J. A. Regulation of DNA double-strand break repair pathway choice. Cell Res. 18, 134-147 (2008
29. Hufnagl A., et al. The link between cell-cycle dependent radiosensitivity and repair pathways: A model based on the local, sister-chromatid conformation dependent switch between NHEJ and HR. DNA Repair (Amst.) 27, 28-39 (2015
30. Aylon Y., Liefshitz B., & Kupiec M. The CDK regulates repair of double-strand breaks by homologous recombination during the cell cycle. EMBO J. 23, 4868-4875 (2004
31. Hentges P., Waller H., Reis C. C., Ferreira M. G., & Doherty A. J. Cdk1 restrains NHEJ through phosphorylation of XRCC4-like factor Xlf1. Cell Rep. 9, 2011-2017 (2014
32. Sorensen C. S., et al. The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair. Nat. Cell Biol. 7, 195-201 (2005
33. Bryant C., Scriven K., & Massey A. J. Inhibition of the checkpoint kinase Chk1 induces DNA damage and cell death in human leukemia and lymphoma cells. Mol. Cancer 13, 147 (2014
34. Sears C. R., & Turchi J. J. Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response (DDR) pathways. J. Biol. Chem. 287, 24263-24272 (2012
35. Gibson B. A., & Kraus W. L. New insights into the molecular and cellular functions of poly(ADP ribose) and PARPs. Nat. Rev. Mol. Cell Biol. 13, 411-424 (2012
36. Noel G., et al. Radiosensitization by the poly(ADP-ribose) polymerase inhibitor 4 amino 1,8-naphthalimide is specific of the S phase of the cell cycle and involves arrest of DNA synthesis. Mol. Cancer Ther. 5, 564-574 (2006
37. Audeh M. W., et al. Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and recurrent ovarian cancer: a proof of concept trial. Lancet 376, 245-251 (2010
38. Fong P. C., et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123-134 (2009
39. Koppensteiner R., et al. Effect of MRE11 loss on PARP-inhibitor sensitivity in endometrial cancer in vitro. PLoS ONE 9, e100041 (2014
40. Wang L., et al. MK 4827, a PARP 1/2 inhibitor, strongly enhances response of human lung and breast cancer xenografts to radiation. Invest. New Drugs 30, 2113-2120 (2012
41. Reiss K. A., et al. A phase I study of veliparib (ABT 888) in combination with low-dose fractionated whole abdominal radiation therapy in patients with advanced solid malignancies and peritoneal carcinomatosis. Clin. Cancer Res. (2014
42. Chow J. P., et al. PARP1 is overexpressed in nasopharyngeal carcinoma and its inhibition enhances radiotherapy. Mol. Cancer Ther. 12, 2517-2528 (2013
43. Nowsheen S., Bonner J. A., & Yang E. S. The poly(ADP-Ribose) polymerase inhibitor ABT 888 reduces radiation-induced nuclear EGFR and augments head and neck tumor response to radiotherapy. Radiother. Oncol. 99, 331-338 (2011
44. Chatterjee P., et al. PARP inhibition sensitizes to low dose-rate radiation TMPRSS2-ERG fusion gene-expressing and PTEN-deficient prostate cancer cells. PLoS ONE 8, e60408 (2013
45. Castri P., et al. Poly(ADP-ribose) polymerase 1 and its cleavage products differentially modulate cellular protection through NF κB dependent signaling. Biochim. Biophys. Acta 1843, 640-651 (2014
46. Hunter J. E., et al. NF κB mediates radio sensitization by the PARP 1 inhibitor, AG 014699. Oncogene 31, 251-264 (2012
47. Feng F. Y., et al. Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer. Breast Cancer Res. Treat. 147, 81-94 (2014
48. OShaughnessy J., et al. Iniparib plus chemotherapy in metastatic triple-negative breast cancer. N. Engl. J. Med. 364, 205-214 (2011
49. Patel A. G., De Lorenzo S. B., Flatten K. S., Poirier G. G., & Kaufmann S. H. Failure of iniparib to inhibit poly(ADP-ribose) polymerase in vitro. Clin. Cancer Res. 18, 1655-1662 (2012
50. Morgan M. A., Parsels L. A., Maybaum J., & Lawrence T. S. Improving the efficacy of chemoradiation with targeted agents. Cancer Discov. 4, 280-291 (2014
51. Takata H., et al. Chromatin compaction protects genomic DNA from radiation damage. PLoS ONE 8, e75622 (2013
52. Chapman J. D., et al. Condensed chromatin and cell inactivation by single-hit kinetics. Radiat. Res. 151, 433-441 (1999
53. Chiolo I., et al. Double-strand breaks in heterochromatin move outside of a dynamic HP1a domain to complete recombinational repair. Cell 144, 732-744 (2011
54. Storch K., et al. Three-dimensional cell growth confers radioresistance by chromatin density modification. Cancer Res. 70, 3925-3934 (2010
55. Jakob B., et al. DNA double-strand breaks in heterochromatin elicit fast repair protein recruitment, histone H2AX phosphorylation and relocation to euchromatin. Nucleic Acids Res. 39, 6489-6499 (2011
56. Chiolo I., Tang J., Georgescu W., & Costes S. V. Nuclear dynamics of radiation-induced foci in euchromatin and heterochromatin. Mutat. Res. 750, 56-66 (2013
57. Jezkova L., et al. Function of chromatin structure and dynamics in DNA damage, repair and misrepair: gamma-rays and protons in action. Appl. Radiat. Isot. 83 (Pt B), 128-136 (2014
58. Falk M., Lukasova E., & Kozubek S. Higher-order chromatin structure in DSB induction, repair and misrepair. Mutat. Res. 704, 88-100 (2010
59. Frame F. M., et al. HDAC inhibitor confers radiosensitivity to prostate stem-like cells. Br. J. Cancer 109, 3023-3033 (2013
60. Pugh J. L., et al. Histone deacetylation critically determines T cell subset radiosensitivity. J. Immunol. 193, 1451-1458 (2014
61. Kruhlak M. J., Celeste A., & Nussenzweig A. Monitoring DNA breaks in optically highlighted chromatin in living cells by laser scanning confocal microscopy. Methods Mol. Biol. 523, 125-140 (2009
62. Becker A., Durante M., Taucher-Scholz G., & Jakob B. ATM alters the otherwise robust chromatin mobility at sites of DNA double-strand breaks (DSBs) in human cells. PLoS ONE 9, e92640 (2014
63. Goodarzi A. A., Jeggo P., & Lobrich M. The influence of heterochromatin on DNA double strand break repair: Getting the strong, silent type to relax. DNA Repair (Amst.) 9, 1273-1282 (2010
64. Goodarzi A. A., & Jeggo P. A. The heterochromatic barrier to DNA double strand break repair: how to get the entry visa. Int. J. Mol. Sci. 13, 11844-11860 (2012
65. Iyengar S., & Farnham P. J. KAP1 protein: an enigmatic master regulator of the genome. J. Biol. Chem. 286, 26267-26276 (2011
66. Lee D. H., et al. Phosphoproteomic analysis reveals that PP4 dephosphorylates KAP 1 impacting the DNA damage response. EMBO J. 31, 2403-2415 (2012
67. Dimitrova N., Chen Y. C., Spector D. L., & De Lange T. 53BP1 promotes non-homologous end joining of telomeres by increasing chromatin mobility. Nature 456, 524-528 (2008
68. Averbeck N. B., & Durante M. Protein acetylation within the cellular response to radiation. J. Cell Physiol. 226, 962-967 (2011
69. Rosato R. R., & Grant S. Histone deacetylase inhibitors in cancer therapy. Cancer Biol. Ther. 2, 30-37 (2003
70. Zhang L., et al. Recent progress in the development of histone deacetylase inhibitors as anti-cancer agents. Mini Rev. Med. Chem. 13, 1999-2013 (2013
71. Camphausen K., et al. Enhancement of in vitro and in vivo tumor cell radiosensitivity by valproic acid. Int. J. Cancer 114, 380-386 (2005
72. Cerna D., Camphausen K., & Tofilon P. J. Histone deacetylation as a target for radiosensitization. Curr. Top. Dev. Biol. 73, 173-204 (2006
73. Shabason J. E., Tofilon P. J., & Camphausen K. HDAC inhibitors in cancer care. Oncology (Williston Park) 24, 180-185 (2010
74. Jung M., et al. Novel HDAC inhibitors with radiosensitizing properties. Radiat. Res. 163, 488-493 (2005
75. Konsoula Z., Velena A., Lee R., Dritschilo A., & Jung M. Histone deacetylase inhibitor: antineoplastic agent and radiation modulator. Adv. Exp. Med. Biol. 720, 171-179 (2011
76. Chinnaiyan P., et al. Postradiation sensitization of the histone deacetylase inhibitor valproic acid. Clin. Cancer Res. 14, 5410-5415 (2008
77. Karagiannis T. C., Kn H., & El-Osta A. The epigenetic modifier, valproic acid, enhances radiation sensitivity. Epigenetics 1, 131-137 (2006
78. Noguchi H., et al. Successful treatment of anaplastic thyroid carcinoma with a combination of oral valproic acid, chemotherapy, radiation and surgery. Endocr. J. 56, 245-249 (2009
79. Ree A. H., et al. Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol. 11, 459-464 (2010
80. Chen H. P., Zhao Y. T., & Zhao T. C. Histone deacetylases and mechanisms of regulation of gene expression. Crit. Rev. Oncog. 20, 35-47 (2015
81. Ren J., et al. HDAC as a therapeutic target for treatment of endometrial cancers. Curr. Pharm. Des. 20, 1847-1856 (2014
82. Nakajima S., & Kitamura M. Bidirectional regulation of NF κB by reactive oxygen species: a role of unfolded protein response. Free Radic. Biol. Med. 65, 162-174 (2013
83. Yoon J. Y., Ishdorj G., Graham B. A., Johnston J. B., & Gibson S. B. Valproic acid enhances fludarabine-induced apoptosis mediated by ROS and involving decreased AKT and ATM activation in B cell lymphoid neoplastic cells. Apoptosis 19, 191-200 (2014
84. Jeong S. G., & Cho G. W. Trichostatin a modulates intracellular reactive oxygen species through SOD2 and FOXO1 in human bone marrow-mesenchymal stem cells. Cell Biochem. Funct. 33, 37-43 (2014
85. Park S., et al. Suberoylanilide hydroxamic acid induces ROS-mediated cleavage of HSP90 in leukemia cells. Cell Stress Chaperones 20, 149-157 (2015
86. Wolf I. M., et al. Histone deacetylases inhibition by SAHA/vorinostat normalizes the glioma microenvironment via xCT equilibration. Sci. Rep. 4, 6226 (2014
87. Sholler G. S., et al. PCI 24781 (abexinostat), a novel histone deacetylase inhibitor, induces reactive oxygen species-dependent apoptosis and is synergistic with bortezomib in neuroblastoma. J. Cancer Ther. Res. 2, 21 (2013
88. Bakkenist C. J., & Kastan M. B. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421, 499-506 (2003
89. Wang H., et al. The HDAC inhibitor depsipeptide transactivates the p53/p21 pathway by inducing DNA damage. DNA Repair (Amst.) 11, 146-156 (2012
90. Blattmann C., et al. Enhancement of radiation response in osteosarcoma and rhabdomyosarcoma cell lines by histone deacetylase inhibition. Int. J. Radiat. Oncol. Biol. Phys. 78, 237-245 (2010
91. Kachhap S. K., et al. Downregulation of homologous recombination DNA repair genes by HDAC inhibition in prostate cancer is mediated through the E2F1 transcription factor. PLoS ONE 5, e11208 (2010
92. Ren J., et al. Epigenetic interventions increase the radiation sensitivity of cancer cells. Curr. Pharm. Des. 20, 1857-1865 (2014
93. Brown S. L., Kolozsvary A., Liu J., Ryu S., & Kim J. H. Histone deacetylase inhibitors protect against and mitigate the lethality of total body irradiation in mice. Radiat. Res. 169, 474-478 (2008
94. Grabiec A. M., Tak P. P., & Reedquist K. A. Function of histone deacetylase inhibitors in inflammation. Crit. Rev. Immunol. 31, 233-263 (2011
95. Kim H. J., & Chuang D. M. HDAC inhibitors mitigate ischemia-induced oligodendrocyte damage: potential roles of oligodendrogenesis, VEGF, and anti-inflammation. Am. J. Transl. Res. 6, 206-223 (2014
96. Felice C., Lewis A., Armuzzi A., Lindsay J. O., & Silver A. Review article: selective histone deacetylase isoforms as potential therapeutic targets in inflammatory bowel diseases. Aliment. Pharmacol. Ther. 41, 26-38 (2015
97. Morris Z. S., & Harari P. M. Interaction of radiation therapy with molecular targeted agents. J. Clin. Oncol. 32, 2886-2893 (2014
98. Chen D. J., & Nirodi C. S. The epidermal growth factor receptor: a role in repair of radiation-induced DNA damage. Clin. Cancer Res. 13, 6555-6560 (2007
99. Kim K., et al. Epidermal growth factor receptor vIII expression in U87 glioblastoma cells alters their proteasome composition, function, and response to irradiation. Mol. Cancer Res. 6, 426-434 (2008
100. Baumann M., et al. EGFR-targeted anti-cancer drugs in radiotherapy: preclinical evaluation of mechanisms. Radiother. Oncol. 83, 238-248 (2007
101. Bonner J. A., et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N. Engl. J. Med. 354, 567-578 (2006
102. Bonner J. A., et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5 year survival data from a phase 3 randomised trial, and relation between cetuximab-induced rash and survival. Lancet Oncol. 11, 21-28 (2010
103. Ang K. K., et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma: RTOG 0522. J. Clin. Oncol. 32, 2940-2950 (2014
104. Debucquoy A., Machiels J. P., McBride W. H., & Haustermans K. Integration of epidermal growth factor receptor inhibitors with preoperative chemoradiation. Clin. Cancer Res. 16, 2709-2714 (2010
105. Kriegs M., et al. Radiosensitization of NSCLC cells by EGFR inhibition is the result of an enhanced p53-dependent G1 arrest. Radiother. Oncol. http://dx.doi.org/10.1016/j.radonc.2015.02.018 (2015
106. Dent P., et al. Stress and radiation-induced activation of multiple intracellular signaling pathways. Radiat. Res. 159, 283-300 (2003
107. Liccardi G., Hartley J. A., & Hochhauser D. EGFR nuclear translocation modulates DNA repair following cisplatin and ionizing radiation treatment. Cancer Res. 71, 1103-1114 (2011
108. Knebel A., Rahmsdorf H. J., Ullrich A., & Herrlich P. Dephosphorylation of receptor tyrosine kinases as target of regulation by radiation, oxidants or alkylating agents. EMBO J. 15, 5314-5325 (1996
109. Schmidt-Ullrich R. K., et al. Radiation-induced proliferation of the human A431 squamous carcinoma cells is dependent on EGFR tyrosine phosphorylation. Oncogene 15, 1191-1197 (1997
110. Kim J., Adam R. M., & Freeman M. R. Trafficking of nuclear heparin-binding epidermal growth factor-like growth factor into an epidermal growth factor receptor-dependent autocrine loop in response to oxidative stress. Cancer Res. 65, 8242-8249 (2005
111. Kefaloyianni E., Gaitanaki C., & Beis I. ERK1/2 and p38-MAPK signalling pathways, through MSK1, are involved in NF κB transactivation during oxidative stress in skeletal myoblasts. Cell Signal. 18, 2238-2251 (2006
112. Papaiahgari S., Zhang Q., Kleeberger S. R., Cho H. Y., & Reddy S. P. Hyperoxia stimulates an Nrf2-ARE transcriptional response via ROS-EGFR-PI3K-Akt/ERK MAP kinase signaling in pulmonary epithelial cells. Antioxid. Redox Signal. 8, 43-52 (2006
113. Han W., & Lo H. W. Landscape of EGFR signaling network in human cancers: biology and therapeutic response in relation to receptor subcellular locations. Cancer Lett. 318, 124-134 (2012
114. Dittmann K., et al. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J. Biol. Chem. 280, 31182-31189 (2005
115. Dittmann K., Mayer C., & Rodemann H. P. Nuclear EGFR as novel therapeutic target: insights into nuclear translocation and function. Strahlenther. Onkol. 186, 1-6 (2010
116. Liccardi G., Hartley J. A., & Hochhauser D. Importance of EGFR/ERCC1 interaction following radiation-induced DNA damage. Clin. Cancer Res. 20, 3496-3506 (2014
117. Javvadi P., et al. Threonine 2609 phosphorylation of the DNA-dependent protein kinase is a critical prerequisite for epidermal growth factor receptor-mediated radiation resistance. Mol. Cancer Res. 10, 1359-1368 (2012
118. Kim I. A., et al. Epigenetic modulation of radiation response in human cancer cells with activated EGFR or HER 2 signaling: potential role of histone deacetylase 6. Radiother. Oncol. 92, 125-132 (2009
119. Dittmann K., Mayer C., Rodemann H. P., & Huber S. M. EGFR cooperates with glucose transporter SGLT1 to enable chromatin remodeling in response to ionizing radiation. Radiother. Oncol. 107, 247-251 (2013
120. Dittmann K., et al. Nuclear epidermal growth factor receptor modulates cellular radio-sensitivity by regulation of chromatin access. Radiother. Oncol. 99, 317-322 (2011
121. Vlashi E., McBride W. H., & Pajonk F. Radiation responses of cancer stem cells. J. Cell Biochem. 108, 339-342 (2009
122. Vlashi E., & Pajonk F. Targeted cancer stem cell therapies start with proper identification of the target. Mol. Cancer Res. 8, 291 (2010
123. Phillips T. M., McBride W. H., & Pajonk F. The response of CD24-/low/CD44+ breast cancer-initiating cells to radiation. J. Natl Cancer Inst. 98, 1777-1785 (2006
124. Bao S., et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444, 756-760 (2006
125. Woodward W. A., et al. WNT/β-catenin mediates radiation resistance of mouse mammary progenitor cells. Proc. Natl Acad. Sci. USA 104, 618-623 (2007
126. Kim Y., Joo K. M., Jin J., & Nam D. H. Cancer stem cells and their mechanism of chemo-radiation resistance. Int. J. Stem Cells 2, 109-114 (2009
127. Rich J. N. Cancer stem cells in radiation resistance. Cancer Res. 67, 8980-8984 (2007
128. Bourguignon L. Y., Shiina M., & Li J. J. Hyaluronan-CD44 interaction promotes oncogenic signaling, microRNA functions, chemoresistance, and radiation resistance in cancer stem cells leading to tumor progression. Adv. Cancer Res. 123, 255-275 (2014
129. McCord A. M., Jamal M., Williams E. S., Camphausen K., & Tofilon P. J. CD133+ glioblastoma stem-like cells are radiosensitive with a defective DNA damage response compared with established cell lines. Clin. Cancer Res. 15, 5145-5153 (2009
130. Zielske S. P., Spalding A. C., Wicha M. S., & Lawrence T. S. Ablation of breast cancer stem cells with radiation. Transl. Oncol. 4, 227-233 (2011
131. Vlashi E., et al. Metabolic state of glioma stem cells and nontumorigenic cells. Proc. Natl Acad. Sci. USA 108, 16062-16067 (2011
132. Diehn M., et al. Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458, 780-783 (2009
133. Zafarana G., & Bristow R. G. Tumor senescence and radioresistant tumor-initiating cells (TICs): let sleeping dogs lie Breast Cancer Res. 12, 111 (2010
134. Dong Q., et al. Radioprotective effects of BMI 1 involve epigenetic silencing of oxidase genes and enhanced DNA repair in normal human keratinocytes. J. Invest. Dermatol. 131, 1216-1225 (2011
135. Pignalosa D., & Durante M. Overcoming resistance of cancer stem cells. Lancet Oncol. 13, e187-e188 (2012
136. Chen T., et al. Effects of heterochromatin in colorectal cancer stem cells on radiosensitivity. Chin. J Cancer 29, 270-276 (2010
137. Vlashi E., & Pajonk F. Cancer stem cells, cancer cell plasticity and radiation therapy. Semin. Cancer Biol. 31, 28-35 (2015
138. Lagadec C., Vlashi E., Della Donna L., Dekmezian C., & Pajonk F. Radiation-induced reprogramming of breast cancer cells. Stem Cells 30, 833-844 (2012
139. Shoshani O., & Zipori D. Stress as a fundamental theme in cell plasticity. Biochim. Biophys. Acta 1849, 371-377 (2015
140. Chlon T. M., et al. High-risk human papillomavirus E6 protein promotes reprogramming of Fanconi anemia patient cells through repression of p53 but does not allow for sustained growth of induced pluripotent stem cells. J. Virol. 88, 11315-11326 (2014
141. Gomez-Casal R., et al. Non-small cell lung cancer cells survived ionizing radiation treatment display cancer stem cell and epithelial-mesenchymal transition phenotypes. Mol. Cancer 12, 94 (2013
142. Patel S. S., Shah K. A., Shah M. J., Kothari K. C., & Rawal R. M. Cancer stem cells and stemness markers in oral squamous cell carcinomas. Asian Pac. J. Cancer Prev. 15, 8549-8556 (2014
143. Venere M., et al. Therapeutic targeting of constitutive PARP activation compromises stem cell phenotype and survival of glioblastoma-initiating cells. Cell Death Differ. 21, 258-269 (2014
144. Gilabert M., et al. Poly(ADP-ribose) polymerase 1 (PARP1) overexpression in human breast cancer stem cells and resistance to olaparib. PLoS ONE 9, e104302 (2014
145. Yoshikawa M., et al. xCT inhibition depletes CD44v-expressing tumor cells that are resistant to EGFR-targeted therapy in head and neck squamous cell carcinoma. Cancer Res. 73, 1855-1866 (2013
146. Greenow K., & Clarke A. R. Controlling the stem cell compartment and regeneration in vivo: the role of pluripotency pathways. Physiol. Rev. 92, 75-99 (2012
147. Takebe N., et al. Targeting Notch, Hedgehog, and Wnt pathways in cancer stem cells: clinical update. Nat. Rev. Clin. Oncol. http://dx.doi.org/10.1038/nrclinonc.2015.61 (2015
148. Mizugaki H., et al. γ-secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer. Br. J. Cancer 106, 1953-1959 (2012
149. Lin J., Zhang X. M., Yang J. C., Ye Y. B., & Luo S. Q. γ-secretase inhibitor I enhances radiosensitivity of glioblastoma cell lines by depleting CD133+ tumor cells. Arch. Med. Res. 41, 519-529 (2010
150. Lagadec C., et al. Radiation-induced Notch signaling in breast cancer stem cells. Int. J. Radiat. Oncol. Biol. Phys. 87, 609-618 (2013
151. Diaz-Padilla I., et al. A phase Ib combination study of RO4929097, a γ-secretase inhibitor, and temsirolimus in patients with advanced solid tumors. Invest. New Drugs 31, 1182-1191 (2013
152. De Strooper B., & Chavez Gutierrez L. Learning by failing: ideas and concepts to tackle γ-secretases in Alzheimer disease and beyond. Annu. Rev. Pharmacol. Toxicol. 55, 419-437 (2015
153. Kim S. H., Kim J. H., & Fried J. Enhancement of the radiation response of cultured tumor cells by chloroquine. Cancer 32, 536-540 (1973
154. Firat E., Weyerbrock A., Gaedicke S., Grosu A. L., & Niedermann G. Chloroquine or chloroquine-PI3K/Akt pathway inhibitor combinations strongly promote gamma-irradiation-induced cell death in primary stem like glioma cells. PLoS ONE 7, e47357 (2012
155. Maycotte P., & Thorburn A. Targeting autophagy in breast cancer. World J. Clin. Oncol. 5, 224-240 (2014
156. Ratikan J. A., Sayre J. W., & Schaue D. Chloroquine engages the immune system to eradicate irradiated breast tumors in mice. Int. J. Radiat. Oncol. Biol. Phys. 87, 761-768 (2013
157. Balic A., et al. Chloroquine targets pancreatic cancer stem cells via inhibition of CXCR4 and hedgehog signaling. Mol. Cancer Ther. 13, 1758-1771 (2014
158. Xiao W., et al. CD44 is a biomarker associated with human prostate cancer radiation sensitivity. Clin. Exp. Metastasis 29, 1-9 (2012
159. Ni J., et al. CD44 variant 6 is associated with prostate cancer metastasis and chemo-/radioresistance. Prostate 74, 602-617 (2014
160. Timmerman L. A., et al. Glutamine sensitivity analysis identifies the xCT antiporter as a common triple-negative breast tumor therapeutic target. Cancer Cell 24, 450-465 (2013
161. Wang F., & Yang Y. Suppression of the xCT-CD44v antiporter system sensitizes triple-negative breast cancer cells to doxorubicin. Breast Cancer Res. Treat. 147, 203-210 (2014
162. Takeuchi S., et al. Sulfasalazine and temozolomide with radiation therapy for newly diagnosed glioblastoma. Neurol. India 62, 42-47 (2014
163. McDonald J. T., et al. Ionizing radiation activates the Nrf2 antioxidant response. Cancer Res. 70, 8886-8895 (2010
164. Bauer A. K., Hill T. 3rd, & Alexander C. M. The involvement of NRF2 in lung cancer. Oxid. Med. Cell Longev. 2013, 746432 (2013
165. Hast B. E., et al. Cancer-derived mutations in KEAP1 impair NRF2 degradation but not ubiquitination. Cancer Res. 74, 808-817 (2014
166. Tao S., et al. Oncogenic KRAS confers chemoresistance by upregulating NRF2. Cancer Res. 74, 7430-7441 (2014
167. Reuter S., Gupta S. C., Chaturvedi M. M., & Aggarwal B. B. Oxidative stress, inflammation, and cancer: how are they linked?. Free Radic. Biol. Med. 49, 1603-1616 (2010
168. Hayes J. D., & Dinkova-Kostova A. T. The Nrf2 regulatory network provides an interface between redox and intermediary metabolism. Trends Biochem. Sci. 39, 199-218 (2014
169. Buettner G. R., Wagner B. A., & Rodgers V. G. Quantitative redox biology: an approach to understand the role of reactive species in defining the cellular redox environment. Cell Biochem. Biophys. 67, 477-483 (2013
170. Ma T., et al. Dual-functional probes for sequential thiol and redox homeostasis sensing in live cells. Analyst 140, 322-329 (2015
171. Kruger A., & Ralser M. ATM is a redox sensor linking genome stability and carbon metabolism. Sci. Signal. 4, pe17 (2011
172. Perry J. J., & Tainer J. A. All stressed out without ATM kinase. Sci. Signal. 4, pe18 (2011
173. Shirwany N. A., & Zou M. H. AMPK: a cellular metabolic and redox sensor. A minireview. Front. Biosci. (Landmark Ed.) 19, 447-474 (2014
174. McBride W. H., et al. A sense of danger from radiation. Radiat. Res. 162, 1-19 (2004
175. Vazquez-Martin A., et al. Repositioning chloroquine and metformin to eliminate cancer stem cell traits in pre-malignant lesions. Drug Resist. Updat. 14, 212-223 (2011
176. Najbauer J., Kraljik N., & Nemeth P. Glioma stem cells: markers, hallmarks and therapeutic targeting by metformin. Pathol. Oncol. Res. 20, 789-797 (2014
177. Skinner H. D., et al. Metformin use and improved response to therapy in rectal cancer. Cancer Med. 2, 99-107 (2013
178. Spratt D. E., et al. Metformin and prostate cancer: reduced development of castration-resistant disease and prostate cancer mortality. Eur. Urol. 63, 709-716 (2013
179. Skinner H. D., et al. Metformin use and improved response to therapy in esophageal adenocarcinoma. Acta Oncol. 52, 1002-1009 (2013
180. Ferro A., et al. Evaluation of diabetic patients with breast cancer treated with metformin during adjuvant radiotherapy. Int. J. Breast Cancer 2013, 659723 (2013
181. Eckers J. C., Kalen A. L., Xiao W., Sarsour E. H., & Goswami P. C. Selenoprotein P inhibits radiation-induced late reactive oxygen species accumulation and normal cell injury. Int. J. Radiat. Oncol. Biol. Phys. 87, 619-625 (2013
182. Gao Z., et al. Late ROS accumulation and radiosensitivity in SOD1-overexpressing human glioma cells. Free Radic. Biol. Med. 45, 1501-1509 (2008
183. Le O. N., et al. Ionizing radiation-induced long-term expression of senescence markers in mice is independent of p53 and immune status. Aging Cell 9, 398-409 (2010
184. Sabin R. J., & Anderson R. M. Cellular Senescence-its role in cancer and the response to ionizing radiation. Genome Integr. 2, 7 (2011
185. Rodier F., et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68-81 (2011
186. Durante M., Reppingen N., & Held K. D. Immunologically augmented cancer treatment using modern radiotherapy. Trends Mol. Med. 19, 565-582 (2013
187. Coppe J. P., et al. Tumor suppressor and aging biomarker p16INK4a induces cellular senescence without the associated inflammatory secretory phenotype. J. Biol. Chem. 286, 36396-36403 (2011
188. Westbrook A. M., et al. The role of tumour necrosis factor-alpha and tumour necrosis factor receptor signalling in inflammation-associated systemic genotoxicity. Mutagenesis 27, 77-86 (2012
189. Schaue D., & McBride W. H. Links between innate immunity and normal tissue radiobiology. Radiation Res. 173, 406-417 (2010
190. Kansara M., et al. Immune response to RB1-regulated senescence limits radiation-induced osteosarcoma formation. J. Clin. Invest. 123, 5351-5360 (2013
191. Klammer H., Mladenov E., Li F., & Iliakis G. Bystander effects as manifestation of intercellular communication of DNA damage and of the cellular oxidative status. Cancer Lett. 356, 58-71 (2015
192. Kim K., et al. High throughput screening of small molecule libraries for modifiers of radiation responses. Int. J. Radiat. Biol. 87, 839-845 (2011
193. Demaria S., Bhardwaj N., McBride W. H., & Formenti S. C. Combining radiotherapy and immunotherapy: a revived partnership. Int. J. Radiat. Oncol. Biol. Phys. 63, 655-666 (2005
194. Formenti S. C., & Demaria S. Radiation therapy to convert the tumor into an in situ vaccine. Int. J. Radiat. Oncol. Biol. Phys. 84, 879-880 (2012
195. Schaue D., Ratikan J. A., Iwamoto K. S., & McBride W. H. Maximizing tumor immunity with fractionated radiation. Int. J. Radiat. Oncol. Biol. Phys. 83, 1306-1310 (2012
196. Schaue D., et al. T cell responses to survivin in cancer patients undergoing radiation therapy. Clin. Cancer Res. 14, 4883-4890 (2008
197. Liao Y. P., Meng W. S., & McBride W. H. Antigen presentation by dendritic cells is affected after irradiation [abstract]. Proc. Am. Assoc. Cancer Res. 43, 480-481 (2002
198. Dewan M. Z., et al. Fractionated but not single-dose radiotherapy induces an immune-mediated abscopal effect when combined with anti CTLA 4 antibody. Clin. Cancer Res. 15, 5379-5388 (2009
199. Snyder A., et al. Genetic basis for clinical response to CTLA 4 blockade in melanoma. N. Engl. J. Med. 371, 2189-2199 (2014
200. Butterfield L. H., et al. Determinant spreading associated with clinical response in dendritic cell-based immunotherapy for malignant melanoma. Clin. Cancer Res. 9, 998-1008 (2003
201. Llosa N. J., et al. The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov. 5, 43-51 (2015
202. Mullen C. A., Coale M. M., Lowe R., & Blaese R. M. Tumors expressing the cytosine deaminase suicide gene can be eliminated in vivo with 5 fluorocytosine and induce protective immunity to wild type tumor. Cancer Res. 54, 1503-1506 (1994
203. Pizova K., et al. Photodynamic therapy for enhancing antitumour immunity. Biomed. Pap. Med. Fac. Univ. Palacky Olomouc Czech. Repub. 156, 93-102 (2012
204. Chen F. H., et al. Radiotherapy decreases vascular density and causes hypoxia with macrophage aggregation in TRAMP C1 prostate tumors. Clin. Cancer Res. 15, 1721-1729 (2009
205. McBride W. H. Phenotype and functions of intratumoral macrophages. Biochim. Biophys. Acta 865, 27-41 (1986
206. Gajewski T. F., et al. Cancer immunotherapy strategies based on overcoming barriers within the tumor microenvironment. Curr. Opin. Immunol. 25, 268-276 (2013
207. Dougherty G. J., & McBride W. H. Immunoregulating activity of tumor-associated macrophages. Cancer Immunol. Immunother. 23, 67-72 (1986
208. Kikuchi N., et al. Nrf2 protects against pulmonary fibrosis by regulating the lung oxidant level and TH1/TH2 balance. Respir. Res. 11, 31 (2010
209. Rockwell C. E., Zhang M., Fields P. E., & Klaassen C. D. TH2 skewing by activation of Nrf2 in CD4+ T cells. J. Immunol. 188, 1630-1637 (2012
210. Schaue D., Xie M. W., Ratikan J. A., & McBride W. H. Regulatory T cells in radiotherapeutic responses. Front. Oncol. 2, 90 (2012
211. Tsai C. S., et al. Macrophages from irradiated tumors express higher levels of iNOS, arginase 1 and COX 2, and promote tumor growth. Int. J. Radiat. Oncol. Biol. Phys. 68, 499-507 (2007
212. Kioi M., et al. Inhibition of vasculogenesis, but not angiogenesis, prevents the recurrence of glioblastoma after irradiation in mice. J. Clin. Invest. 120, 694-705 (2010
213. Tseng D., Vasquez-Medrano D. A., & Brown J. M. Targeting SDF 1/CXCR4 to inhibit tumour vasculature for treatment of glioblastomas. Br. J. Cancer 104, 1805-1809 (2011
214. Chen F. H., et al. Combination of vessel-targeting agents and fractionated radiation therapy: the role of the SDF 1/CXCR4 pathway. Int. J. Radiat. Oncol. Biol. Phys. 86, 777-784 (2013
215. Brown J. M. Vasculogenesis: a crucial player in the resistance of solid tumours to radiotherapy. Br. J. Radiol. 87, 20130686 (2014
216. Xu J., et al. CSF1R signaling blockade stanches tumor-infiltrating myeloid cells and improves the efficacy of radiotherapy in prostate cancer. Cancer Res. 73, 2782-2794 (2013
217. Chiang C. S., et al. Irradiation promotes an M2 macrophage phenotype in tumor hypoxia. Front. Oncol. 2, 89 (2012
218. Ahn G. O., & Brown J. M. Influence of bone marrow-derived hematopoietic cells on the tumor response to radiotherapy: experimental models and clinical perspectives. Cell Cycle 8, 970-976 (2009
219. Mantovani A., & Allavena P. The interaction of anticancer therapies with tumor-associated macrophages. J. Exp. Med. 212, 435-445 (2015
220. Tsai J. H., et al. Ionizing radiation inhibits tumor neovascularization by inducing ineffective angiogenesis. Cancer Biol. Ther. 4, 1395-1400 (2005
221. Pardoll D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252-264 (2012
222. Johnson D. B., Rioth M. J., & Horn L. Immune checkpoint inhibitors in NSCLC. Curr. Treat. Options Oncol. 15, 658-669 (2014
223. Demaria S., et al. Immune-mediated inhibition of metastases after treatment with local radiation and CTLA 4 blockade in a mouse model of breast cancer. Clin. Cancer Res. 11, 728-734 (2005
224. Pilones K. A., Vanpouille-Box C., & Demaria S. Combination of radiotherapy and immune checkpoint inhibitors. Semin. Radiat. Oncol. 25, 28-33 (2015
225. Deng L., et al. Irradiation and anti PD L1 treatment synergistically promote antitumor immunity in mice. J. Clin. Invest. 124, 687-695 (2014
226. Stamell E. F., Wolchok J. D., Gnjatic S., Lee N. Y., & Brownell I. The abscopal effect associated with a systemic anti-melanoma immune response. Int. J. Radiat. Oncol. Biol. Phys. 85, 293-295 (2013
227. Hiniker S. M., et al. A systemic complete response of metastatic melanoma to local radiation and immunotherapy. Transl. Oncol. 5, 404-407 (2012
228. Postow M. A., Harding J., & Wolchok J. D. Targeting immune checkpoints: releasing the restraints on anti-tumor immunity for patients with melanoma. Cancer J. 18, 153-159 (2012