Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening

Authors: Zongxiang Zhou, Manishha Patel, Nicholas Ng, Mindy H Hsieh, Anthony P Orth, John R Walker, Serge Batalov, Jennifer L Harris, Jun Liu

Published in: BMC Cancer | Issue 1/2014

Login to get access

Abstract

Background

MYC family members are among the most frequently deregulated oncogenes in human cancers, yet direct therapeutic targeting of MYC in cancer has been challenging thus far. Synthetic lethality provides an opportunity for therapeutic intervention of MYC-driven cancers.

Methods

A pooled kinase shRNA library screen was performed and next-generation deep sequencing efforts identified that PRKDC was synthetically lethal in cells overexpressing MYC. Genes and proteins of interest were knocked down or inhibited using RNAi technology and small molecule inhibitors, respectively. Quantitative RT-PCR using TaqMan probes examined mRNA expression levels and cell viability was assessed using CellTiter-Glo (Promega). Western blotting was performed to monitor different protein levels in the presence or absence of RNAi or compound treatment. Statistical significance of differences among data sets were determined using unpaired t test (Mann–Whitney test) or ANOVA.

Results

Inhibition of PRKDC using RNAi (RNA interference) or small molecular inhibitors preferentially killed MYC-overexpressing human lung fibroblasts. Moreover, inducible PRKDC knockdown decreased cell viability selectively in high MYC-expressing human small cell lung cancer cell lines. At the molecular level, we found that inhibition of PRKDC downregulated MYC mRNA and protein expression in multiple cancer cell lines. In addition, we confirmed that overexpression of MYC family proteins induced DNA double-strand breaks; our results also revealed that PRKDC inhibition in these cells led to an increase in DNA damage levels.

Conclusions

Our data suggest that the synthetic lethality between PRKDC and MYC may in part be due to PRKDC dependent modulation of MYC expression, as well as MYC-induced DNA damage where PRKDC plays a key role in DNA damage repair.
Appendix
Available only for authorised users
Literature
1.
Roberts PJ, Der CJ: Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007, 26 (22): 3291-3310. 10.1038/sj.onc.1210422.CrossRefPubMed
2.
3.
Beroukhim R, Mermel CH, Porter D, Wei G, Raychaudhuri S, Donovan J, Barretina J, Boehm JS, Dobson J, Urashima M, Mc Henry K, Pinchback R, Ligon A, Cho Y, Haery L, Greulich H, Reich M, Winckler W, Lawrence M, Weir B, Tanaka K, Chiang D, Bass A, Loo A, Hoffman C, Prensner J, Liefeld T, Gao Q, Yecies D, Signoretti S: The landscape of somatic copy-number alteration across human cancers. Nature. 2010, 463 (7283): 899-905. 10.1038/nature08822.CrossRefPubMedPubMedCentral
4.
5.
Larsson LG, Henriksson MA: The Yin and Yang functions of the Myc oncoprotein in cancer development and as targets for therapy. Exp Cell Res. 2010, 316 (8): 1429-1437. 10.1016/j.yexcr.2010.03.025.CrossRefPubMed
6.
Toyoshima M, Howie HL, Imakura M, Walsh RM, Annis JE, Chang AN, Frazier J, Chau BN, Loboda A, Linsley PS, Cleary M, Park J, Grandori C: Functional genomics identifies therapeutic targets for MYC-driven cancer. Proc Natl Acad Sci U S A. 2012, 109 (24): 9545-9550. 10.1073/pnas.1121119109.CrossRefPubMedPubMedCentral
7.
Jiang H, Bower KE, Beuscher AE, Zhou B, Bobkov AA, Olson AJ, Vogt PK: Stabilizers of the Max homodimer identified in virtual ligand screening inhibit Myc function. Mol Pharmacol. 2009, 76 (3): 491-502. 10.1124/mol.109.054858.CrossRefPubMedPubMedCentral
8.
Nair SK, Burley SK: Structural aspects of interactions within the Myc/Max/Mad network. Curr Top Microbiol Immunol. 2006, 302: 123-143.PubMed
9.
Amati B, Littlewood TD, Evan GI, Land H: The c-Myc protein induces cell cycle progression and apoptosis through dimerization with Max. EMBO J. 1993, 12 (13): 5083-5087.PubMedPubMedCentral
10.
Ferre-D'Amare AR, Prendergast GC, Ziff EB, Burley SK: Recognition by Max of its cognate DNA through a dimeric b/HLH/Z domain. Nature. 1993, 363 (6424): 38-45. 10.1038/363038a0.CrossRefPubMed
11.
Soucek L, Nasi S, Evan GI: Omomyc expression in skin prevents Myc-induced papillomatosis. Cell Death Differ. 2004, 11 (9): 1038-1045. 10.1038/sj.cdd.4401443.CrossRefPubMed
12.
Soucek L, Jucker R, Panacchia L, Ricordy R, Tato F, Nasi S: Omomyc, a potential Myc dominant negative, enhances Myc-induced apoptosis. Cancer Res. 2002, 62 (12): 3507-3510.PubMed
13.
Savino M, Annibali D, Carucci N, Favuzzi E, Cole MD, Evan GI, Soucek L, Nasi S: The action mechanism of the Myc inhibitor termed Omomyc may give clues on how to target Myc for cancer therapy. PLoS One. 2011, 6 (7): e22284-10.1371/journal.pone.0022284.CrossRefPubMedPubMedCentral
14.
Soucek L, Whitfield JR, Sodir NM, Masso-Valles D, Serrano E, Karnezis AN, Swigart LB, Evan GI: Inhibition of Myc family proteins eradicates KRas-driven lung cancer in mice. Genes Dev. 2013, 27 (5): 504-513. 10.1101/gad.205542.112.CrossRefPubMedPubMedCentral
15.
Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, Karnezis AN, Swigart LB, Nasi S, Evan GI: Modelling Myc inhibition as a cancer therapy. Nature. 2008, 455 (7213): 679-683. 10.1038/nature07260.CrossRefPubMedPubMedCentral
16.
Kaelin WG: The concept of synthetic lethality in the context of anticancer therapy. Nat Rev Cancer. 2005, 5 (9): 689-698. 10.1038/nrc1691.CrossRefPubMed
17.
Chan DA, Giaccia AJ: Harnessing synthetic lethal interactions in anticancer drug discovery. Nat Rev Drug Discov. 2011, 10 (5): 351-364. 10.1038/nrd3374.CrossRefPubMedPubMedCentral
18.
Polyak K, Garber J: Targeting the missing links for cancer therapy. Nat Med. 2011, 17 (3): 283-284. 10.1038/nm0311-283.CrossRefPubMed
19.
Fong PC, Boss DS, Yap TA, Tutt A, Wu P, Mergui-Roelvink M, Mortimer P, Swaisland H, Lau A, O'Connor MJ, Ashworth A, Carmichael J, Kaye SB, Schellens JH, de Bono JS: Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N Engl J Med. 2009, 361 (2): 123-134. 10.1056/NEJMoa0900212.CrossRefPubMed
20.
Fong PC, Yap TA, Boss DS, Carden CP, Mergui-Roelvink M, Gourley C, De Greve J, Lubinski J, Shanley S, Messiou C, A'Hern R, Tutt A, Ashworth A, Stone J, Carmichael J, Schellens JH, de Bono JS, Kaye SB: Poly(ADP)-ribose polymerase inhibition: frequent durable responses in BRCA carrier ovarian cancer correlating with platinum-free interval. J Clin Oncol. 2010, 28 (15): 2512-2519. 10.1200/JCO.2009.26.9589.CrossRefPubMed
21.
Tutt A, Robson M, Garber JE, Domchek SM, Audeh MW, Weitzel JN, Friedlander M, Arun B, Loman N, Schmutzler RK, Wardley A, Mitchell G, Earl H, Wickens M, Carmichael J: Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial. Lancet. 2010, 376 (9737): 235-244. 10.1016/S0140-6736(10)60892-6.CrossRefPubMed
22.
Gelmon KA, Tischkowitz M, Mackay H, Swenerton K, Robidoux A, Tonkin K, Hirte H, Huntsman D, Clemons M, Gilks B, Yerushalmi R, Macpherson E, Carmichael J, Oza A: Olaparib in patients with recurrent high-grade serous or poorly differentiated ovarian carcinoma or triple-negative breast cancer: a phase 2, multicentre, open-label, non-randomised study. Lancet Oncol. 2011, 12 (9): 852-861. 10.1016/S1470-2045(11)70214-5.CrossRefPubMed
23.
Mohr S, Bakal C, Perrimon N: Genomic screening with RNAi: results and challenges. Annu Rev Biochem. 2010, 79: 37-64. 10.1146/annurev-biochem-060408-092949.CrossRefPubMedPubMedCentral
24.
DeFazio LG, Stansel RM, Griffith JD, Chu G: Synapsis of DNA ends by DNA-dependent protein kinase. EMBO J. 2002, 21 (12): 3192-3200. 10.1093/emboj/cdf299.CrossRefPubMedPubMedCentral
25.
Ma Y, Lu H, Tippin B, Goodman MF, Shimazaki N, Koiwai O, Hsieh CL, Schwarz K, Lieber MR: A biochemically defined system for mammalian nonhomologous DNA end joining. Mol Cell. 2004, 16 (5): 701-713. 10.1016/j.molcel.2004.11.017.CrossRefPubMed
26.
Wiederschain D, Wee S, Chen L, Loo A, Yang G, Huang A, Chen Y, Caponigro G, Yao YM, Lengauer C, Sellers WR, Benson JD: Single-vector inducible lentiviral RNAi system for oncology target validation. Cell Cycle. 2009, 8 (3): 498-504. 10.4161/cc.8.3.7701.CrossRefPubMed
27.
Molenaar JJ, Ebus ME, Geerts D, Koster J, Lamers F, Valentijn LJ, Westerhout EM, Versteeg R, Caron HN: Inactivation of CDK2 is synthetically lethal to MYCN over-expressing cancer cells. Proc Natl Acad Sci U S A. 2009, 106 (31): 12968-12973. 10.1073/pnas.0901418106.CrossRefPubMedPubMedCentral
28.
Rottmann S, Wang Y, Nasoff M, Deveraux QL, Quon KC: A TRAIL receptor-dependent synthetic lethal relationship between MYC activation and GSK3beta/FBW7 loss of function. Proc Natl Acad Sci U S A. 2005, 102 (42): 15195-15200. 10.1073/pnas.0505114102.CrossRefPubMedPubMedCentral
29.
Jackson SP: Sensing and repairing DNA double-strand breaks. Carcinogenesis. 2002, 23 (5): 687-696. 10.1093/carcin/23.5.687.CrossRefPubMed
30.
Park SJ, Oh EJ, Yoo MA, Lee SH: Involvement of DNA-dependent protein kinase in regulation of stress-induced JNK activation. DNA Cell Biol. 2001, 20 (10): 637-645. 10.1089/104454901753340622.CrossRefPubMed
31.
Peterson SR, Kurimasa A, Oshimura M, Dynan WS, Bradbury EM, Chen DJ: Loss of the catalytic subunit of the DNA-dependent protein kinase in DNA double-strand-break-repair mutant mammalian cells. Proc Natl Acad Sci U S A. 1995, 92 (8): 3171-3174. 10.1073/pnas.92.8.3171.CrossRefPubMedPubMedCentral
32.
An J, Yang DY, Xu QZ, Zhang SM, Huo YY, Shang ZF, Wang Y, Wu DC, Zhou PK: DNA-dependent protein kinase catalytic subunit modulates the stability of c-Myc oncoprotein. Mol Cancer. 2008, 7: 32-10.1186/1476-4598-7-32.CrossRefPubMedPubMedCentral
33.
Karlsson A, Deb-Basu D, Cherry A, Turner S, Ford J, Felsher DW: Defective double-strand DNA break repair and chromosomal translocations by MYC overexpression. Proc Natl Acad Sci U S A. 2003, 100 (17): 9974-9979. 10.1073/pnas.1732638100.CrossRefPubMedPubMedCentral
34.
Li Z, Owonikoko TK, Sun SY, Ramalingam SS, Doetsch PW, Xiao ZQ, Khuri FR, Curran WJ, Deng X: c-Myc suppression of DNA double-strand break repair. Neoplasia (New York, NY). 2012, 14 (12): 1190-1202.CrossRef
35.
Leahy JJ, Golding BT, Griffin RJ, Hardcastle IR, Richardson C, Rigoreau L, Smith GC: Identification of a highly potent and selective DNA-dependent protein kinase (DNA-PK) inhibitor (NU7441) by screening of chromenone libraries. Bioorg Med Chem Lett. 2004, 14 (24): 6083-6087. 10.1016/j.bmcl.2004.09.060.CrossRefPubMed
36.
Munck JM, Batey MA, Zhao Y, Jenkins H, Richardson CJ, Cano C, Tavecchio M, Barbeau J, Bardos J, Cornell L, Griffin RJ, Menear K, Slade A, Thommes P, Martin NM, Newell DR, Smith GC, Curtin NJ: Chemosensitization of cancer cells by KU-0060648, a dual inhibitor of DNA-PK and PI-3 K. Mol Cancer Ther. 2012, 11 (8): 1789-1798. 10.1158/1535-7163.MCT-11-0535.CrossRefPubMedPubMedCentral
37.
Iijima S, Teraoka H, Date T, Tsukada K: DNA-activated protein kinase in Raji Burkitt's lymphoma cells. Phosphorylation of c-Myc oncoprotein. Eur J Biochem. 1992, 206 (2): 595-603. 10.1111/j.1432-1033.1992.tb16964.x.CrossRefPubMed
38.
An J, Xu QZ, Sui JL, Bai B, Zhou PK: Downregulation of c-myc protein by siRNA-mediated silencing of DNA-PKcs in HeLa cells. Int J Cancer. 2005, 117 (4): 531-537. 10.1002/ijc.21093.CrossRefPubMed
39.
Ray S, Atkuri KR, Deb-Basu D, Adler AS, Chang HY, Herzenberg LA, Felsher DW: MYC can induce DNA breaks in vivo and in vitro independent of reactive oxygen species. Cancer Res. 2006, 66 (13): 6598-6605. 10.1158/0008-5472.CAN-05-3115.CrossRefPubMed
40.
Celeste A, Petersen S, Romanienko PJ, Fernandez-Capetillo O, Chen HT, Sedelnikova OA, Reina-San-Martin B, Coppola V, Meffre E, Difilippantonio MJ, Redon C, Pilch DR, Olaru A, Eckhaus M, Camerini-Otero RD, Tessarollo L, Livak F, Manova K, Bonner WM, Nussenzweig MC, Nussenzweig A: Genomic instability in mice lacking histone H2AX. Science. 2002, 296 (5569): 922-927. 10.1126/science.1069398.CrossRefPubMedPubMedCentral
41.
Celeste A, Fernandez-Capetillo O, Kruhlak MJ, Pilch DR, Staudt DW, Lee A, Bonner RF, Bonner WM, Nussenzweig A: Histone H2AX phosphorylation is dispensable for the initial recognition of DNA breaks. Nat Cell Biol. 2003, 5 (7): 675-679. 10.1038/ncb1004.CrossRefPubMed
42.
Valdiglesias V, Giunta S, Fenech M, Neri M, Bonassi S: gammaH2AX as a marker of DNA double strand breaks and genomic instability in human population studies. Mutat Res. 2013, 735 (1): 24-40.CrossRef
43.
Montecucco A, Biamonti G: Cellular response to etoposide treatment. Cancer Lett. 2007, 252 (1): 9-18. 10.1016/j.canlet.2006.11.005.CrossRefPubMed
44.
Arvanitis C, Felsher DW: Conditional transgenic models define how MYC initiates and maintains tumorigenesis. Semin Cancer Biol. 2006, 16 (4): 313-317. 10.1016/j.semcancer.2006.07.012.CrossRefPubMed
45.
Zuber J, Shi J, Wang E, Rappaport AR, Herrmann H, Sison EA, Magoon D, Qi J, Blatt K, Wunderlich M, Taylor MJ, Johns C, Chicas A, Mulloy JC, Kogan SC, Brown P, Valent P, Bradner JE, Lowe SW, Vakoc CR: RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia. Nature. 2011, 478 (7370): 524-528. 10.1038/nature10334.CrossRefPubMedPubMedCentral
46.
Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, Qi J, Qi J, Chesi M, Schinzel AC, McKeown MR, Heffernan TP, Vakoc CR, Bergsagel PL, Ghobrial IM, Richardson PG, Young RA, Hahn WC, Anderson KC, Kung AL, Bradner JE, Mitsiades CS: BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011, 146 (6): 904-917. 10.1016/j.cell.2011.08.017.CrossRefPubMedPubMedCentral
47.
Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ: Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proc Natl Acad Sci U S A. 2011, 108 (40): 16669-16674. 10.1073/pnas.1108190108.CrossRefPubMedPubMedCentral
48.
Wang Y, Engels IH, Knee DA, Nasoff M, Deveraux QL, Quon KC: Synthetic lethal targeting of MYC by activation of the DR5 death receptor pathway. Cancer Cell. 2004, 5 (5): 501-512. 10.1016/S1535-6108(04)00113-8.CrossRefPubMed
49.
Goga A, Yang D, Tward AD, Morgan DO, Bishop JM: Inhibition of CDK1 as a potential therapy for tumors over-expressing MYC. Nat Med. 2007, 13 (7): 820-827. 10.1038/nm1606.CrossRefPubMed
50.
Murga M, Campaner S, Lopez-Contreras AJ, Toledo LI, Soria R, Montana MF, D'Artista L, Schleker T, Guerra C, Garcia E, Barbacid M, Hidalgo M, Amati B, Fernandez-Capetillo O: Exploiting oncogene-induced replicative stress for the selective killing of Myc-driven tumors. Nat Struct Mol Biol. 2011, 18 (12): 1331-1335. 10.1038/nsmb.2189.CrossRefPubMedPubMedCentral
51.
Liu L, Ulbrich J, Muller J, Wustefeld T, Aeberhard L, Kress TR, Muthalagu N, Rycak L, Rudalska R, Moll R, Kempa S, Zender L, Eilers M, Murphy DJ: Deregulated MYC expression induces dependence upon AMPK-related kinase 5. Nature. 2012, 483 (7391): 608-612. 10.1038/nature10927.CrossRefPubMed
52.
Kessler JD, Kahle KT, Sun T, Meerbrey KL, Schlabach MR, Schmitt EM, Skinner SO, Xu Q, Li MZ, Hartman ZC, Rao M, Yu P, Dominguez-Vidana R, Liang AC, Solimini NL, Bernardi RJ, Yu B, Hsu T, Golding I, Luo J, Osborne CK, Creighton CJ, Hilsenbeck SG, Schiff R, Shaw CA, Elledge SJ, Westbrook TF: A SUMOylation-dependent transcriptional subprogram is required for Myc-driven tumorigenesis. Science. 2012, 335 (6066): 348-353. 10.1126/science.1212728.CrossRefPubMed
53.
Furgason JM, el Bahassi M: Targeting DNA repair mechanisms in cancer. Pharmacol Ther. 2013, 137 (3): 298-308. 10.1016/j.pharmthera.2012.10.009.CrossRefPubMed
54.
Yang D, Liu H, Goga A, Kim S, Yuneva M, Bishop JM: Therapeutic potential of a synthetic lethal interaction between the MYC proto-oncogene and inhibition of aurora-B kinase. Proc Natl Acad Sci U S A. 2010, 107 (31): 13836-13841. 10.1073/pnas.1008366107.CrossRefPubMedPubMedCentral
55.
Gao Y, Chaudhuri J, Zhu C, Davidson L, Weaver DT, Alt FW: A targeted DNA-PKcs-null mutation reveals DNA-PK-independent functions for KU in V(D)J recombination. Immunity. 1998, 9 (3): 367-376. 10.1016/S1074-7613(00)80619-6.CrossRefPubMed
56.
van der Burg M, Ijspeert H, Verkaik NS, Turul T, Wiegant WW, Morotomi-Yano K, Mari PO, Tezcan I, Chen DJ, Zdzienicka MZ, van Dongen JJ, van Gent DC: A DNA-PKcs mutation in a radiosensitive T-B- SCID patient inhibits Artemis activation and nonhomologous end-joining. J Clin Invest. 2009, 119 (1): 91-98.PubMed
57.
Blunt T, Finnie NJ, Taccioli GE, Smith GC, Demengeot J, Gottlieb TM, Mizuta R, Varghese AJ, Alt FW, Jeggo PA, Jackson SP: Defective DNA-dependent protein kinase activity is linked to V(D)J recombination and DNA repair defects associated with the murine scid mutation. Cell. 1995, 80 (5): 813-823. 10.1016/0092-8674(95)90360-7.CrossRefPubMed
58.
Bosma GC, Custer RP, Bosma MJ: A severe combined immunodeficiency mutation in the mouse. Nature. 1983, 301 (5900): 527-530. 10.1038/301527a0.CrossRefPubMed
59.
Kirchgessner CU, Patil CK, Evans JW, Cuomo CA, Fried LM, Carter T, Oettinger MA, Brown JM: DNA-dependent kinase (p350) as a candidate gene for the murine SCID defect. Science. 1995, 267 (5201): 1178-1183. 10.1126/science.7855601.CrossRefPubMed
60.
Taccioli GE, Amatucci AG, Beamish HJ, Gell D, Xiang XH, Torres Arzayus MI, Priestley A, Jackson SP, Marshak Rothstein A, Jeggo PA, Herrera VL: Targeted disruption of the catalytic subunit of the DNA-PK gene in mice confers severe combined immunodeficiency and radiosensitivity. Immunity. 1998, 9 (3): 355-366. 10.1016/S1074-7613(00)80618-4.CrossRefPubMed
61.
Zhao Y, Thomas HD, Batey MA, Cowell IG, Richardson CJ, Griffin RJ, Calvert AH, Newell DR, Smith GC, Curtin NJ: Preclinical evaluation of a potent novel DNA-dependent protein kinase inhibitor NU7441. Cancer Res. 2006, 66 (10): 5354-5362. 10.1158/0008-5472.CAN-05-4275.CrossRefPubMed
62.
Engelman JA, Chen L, Tan X, Crosby K, Guimaraes AR, Upadhyay R, Maira M, McNamara K, Perera SA, Song Y, Chirieac LR, Kaur R, Lightbown A, Simendinger J, Li T, Padera RF, Garcia-Echeverria C, Weissleder R, Mahmood U, Cantley LC, Wong KK: Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancers. Nat Med. 2008, 14 (12): 1351-1356. 10.1038/nm.1890.CrossRefPubMedPubMedCentral
63.
Serra V, Markman B, Scaltriti M, Eichhorn PJ, Valero V, Guzman M, Botero ML, Llonch E, Atzori F, Di Cosimo S, Maira M, Garcia-Echeverria C, Parra JL, Arribas J, Baselga J: NVP-BEZ235, a dual PI3K/mTOR inhibitor, prevents PI3K signaling and inhibits the growth of cancer cells with activating PI3K mutations. Cancer Res. 2008, 68 (19): 8022-8030. 10.1158/0008-5472.CAN-08-1385.CrossRefPubMed
64.
Maira SM, Stauffer F, Brueggen J, Furet P, Schnell C, Fritsch C, Brachmann S, Chene P, De Pover A, Schoemaker K, Fabbro D, Gabriel D, Simonen M, Murphy L, Finan P, Sellers W, Garcia-Echeverria C: Identification and characterization of NVP-BEZ235, a new orally available dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor with potent in vivo antitumor activity. Mol Cancer Ther. 2008, 7 (7): 1851-1863. 10.1158/1535-7163.MCT-08-0017.CrossRefPubMed
65.
66.
Garcia-Echeverria C, Sellers WR: Drug discovery approaches targeting the PI3K/Akt pathway in cancer. Oncogene. 2008, 27 (41): 5511-5526. 10.1038/onc.2008.246.CrossRefPubMed
67.
Anderson CW, Carter TH: The DNA-activated protein kinase – DNA-PK. Curr Top Microbiol Immunol. 1996, 217: 91-111.PubMed
68.
Jackson SP: DNA damage detection by DNA dependent protein kinase and related enzymes. Cancer Surv. 1996, 28: 261-279.PubMed
69.
Shimomura A, Takasaki A, Nomura R, Hayashi N, Senda T: Identification of DNA-dependent protein kinase catalytic subunit as a novel interaction partner of lymphocyte enhancer factor 1. Med Mol Morphol. 2013, 46 (1): 14-19. 10.1007/s00795-012-0002-z.CrossRefPubMed
70.
Huang J, Nueda A, Yoo S, Dynan WS: Heat shock transcription factor 1 binds selectively in vitro to Ku protein and the catalytic subunit of the DNA-dependent protein kinase. J Biol Chem. 1997, 272 (41): 26009-26016. 10.1074/jbc.272.41.26009.CrossRefPubMed
71.
Brenner JC, Ateeq B, Li Y, Yocum AK, Cao Q, Asangani IA, Patel S, Wang X, Liang H, Yu J, Palanisamy N, Siddiqui J, Yan W, Cao X, Mehra R, Sabolch A, Basrur V, Lonigro RJ, Yang J, Tomlins SA, Maher CA, Elenitoba-Johnson KS, Hussain M, Navone NM, Pienta KJ, Varambally S, Feng FY, Chinnaiyan AM: Mechanistic rationale for inhibition of poly(ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer. Cancer Cell. 2011, 19 (5): 664-678. 10.1016/j.ccr.2011.04.010.CrossRefPubMedPubMedCentral
Metadata
Title
Identification of synthetic lethality of PRKDC in MYC-dependent human cancers by pooled shRNA screening
Authors
Zongxiang Zhou
Manishha Patel
Nicholas Ng
Mindy H Hsieh
Anthony P Orth
John R Walker
Serge Batalov
Jennifer L Harris
Jun Liu
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-944

Other articles of this Issue 1/2014

BMC Cancer 1/2014 Go to the issue

Research article

Pharmacological inhibition of EZH2 as a promising differentiation therapy in embryonal RMS

Research article

Evaluation of superparamagnetic iron oxide-polymer composite microcapsules for magnetic resonance-guided high-intensity focused ultrasound cancer surgery

Research article

LEIGClong non-coding RNA acts as a tumor suppressor in gastric carcinoma by inhibiting the epithelial-to-mesenchymal transition

Research article

Molecular characterisation of isogenic taxane resistant cell lines identify novel drivers of drug resistance

Research article

Ratio of n-3/n-6 PUFAs and risk of breast cancer: a meta-analysis of 274135 adult females from 11 independent prospective studies

Study protocol

Effect of physical therapy on breast cancer related lymphedema: protocol for a multicenter, randomized, single-blind, equivalence trial
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits