Identification of a novel synthetic lethality of combined inhibition of hedgehog and PI3K signaling in rhabdomyosarcoma

Oncotarget

Volumn 6, Issue 11, 2015, Pages 8722-8735

  Graab, Ulrike ^a   Hahn, Heidi ^b   Fulda, Simone ^a,c  

^a GOETHE UNIVERSITY   (Germany)

^b UNIVERSITY MEDICAL CENTER GÖTTINGEN   (Germany)

^c GERMAN CANCER RESEARCH CENTER DKFZ   (Germany)

Author keywords

Apoptosis; Hedgehog; PI3K; Rhabdomyosarcoma

Indexed keywords

2 (4 HYDROXYPHENYL) 4 MORPHOLINOPYRIDO[3',2':4,5]FURO[3,2 D]PYRIMIDINE; ANTINEOPLASTIC AGENT; CASPASE 8; CASPASE 9; GANT 61; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN BAK; PROTEIN BAX; PROTEIN BCL 2; PROTEIN NOXA; PROTEIN P35; SONIC HEDGEHOG PROTEIN; UNCLASSIFIED DRUG; AKT1 PROTEIN, HUMAN; APOPTOSIS REGULATORY PROTEIN; BENZYLOXYCARBONYLVALYL-ALANYL-ASPARTYL FLUOROMETHYL KETONE; CASPASE; FURAN DERIVATIVE; GLI1 PROTEIN, HUMAN; GLI2 PROTEIN, HUMAN; KRUPPEL LIKE FACTOR; MTOR PROTEIN, HUMAN; NUCLEAR PROTEIN; PEPTIDE CHLOROMETHYL KETONE; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; PYRIDINE DERIVATIVE; PYRIMIDINE DERIVATIVE; SHH PROTEIN, HUMAN; TARGET OF RAPAMYCIN KINASE; TRANSCRIPTION FACTOR; TRANSCRIPTION FACTOR GLI1; TUMOR PROTEIN;

APOPTOSIS; ARTICLE; CANCER PROGNOSIS; CELL VIABILITY; CONCENTRATION RESPONSE; CONTROLLED STUDY; DRUG EFFICACY; DRUG POTENTIATION; GENE; GENE OVEREXPRESSION; GENE TARGETING; GLI1 GENE; GLI2 GENE; GROWTH INHIBITION; HUMAN; HUMAN CELL; PROTEIN CLEAVAGE; PROTEIN EXPRESSION; PROTEIN FUNCTION; PROTEIN PHOSPHORYLATION; PTCH GENE; RHABDOMYOSARCOMA; TUMOR GROWTH; UPREGULATION; ANIMAL; ANTAGONISTS AND INHIBITORS; BIOSYNTHESIS; CHICK EMBRYO; DRUG EFFECTS; DRUG SCREENING; EMBRYONAL RHABDOMYOSARCOMA; GENE EXPRESSION REGULATION; GENETICS; METABOLISM; MOLECULARLY TARGETED THERAPY; PATHOLOGY; PHYSIOLOGY; SIGNAL TRANSDUCTION; TUMOR CELL LINE;

AMINO ACID CHLOROMETHYL KETONES; ANIMALS; APOPTOSIS; APOPTOSIS REGULATORY PROTEINS; CASPASES; CELL LINE, TUMOR; CHICK EMBRYO; DRUG SCREENING ASSAYS, ANTITUMOR; DRUG SYNERGISM; FURANS; GENE EXPRESSION REGULATION, NEOPLASTIC; HEDGEHOG PROTEINS; HUMANS; KRUPPEL-LIKE TRANSCRIPTION FACTORS; MOLECULAR TARGETED THERAPY; NEOPLASM PROTEINS; NUCLEAR PROTEINS; PHOSPHATIDYLINOSITOL 3-KINASES; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS C-AKT; PYRIDINES; PYRIMIDINES; RHABDOMYOSARCOMA, ALVEOLAR; RHABDOMYOSARCOMA, EMBRYONAL; SIGNAL TRANSDUCTION; TOR SERINE-THREONINE KINASES; TRANSCRIPTION FACTORS; ZINC FINGER PROTEIN GLI1;

EID: 84928752041     PISSN: None     EISSN: 19492553     Source Type: Journal    
DOI: 10.18632/oncotarget.2726     Document Type: Article

References (54)

1. Gallego Melcon S, Sanchez de Toledo Codina J. Molecular biology of rhabdomyosarcoma. Clin Transl Oncol. 2007;9:415-419.
2. Parham DM, Barr FG. Classification of rhabdomyosarcoma and its molecular basis. Adv Anat Pathol. 2013;20:387-397.
3. Bridge JA, Liu J, Weibolt V, Baker KS, Perry D, Kruger R, Qualman S, Barr F, Sorensen P, Triche T, Suijkerbuijk R. Novel genomic imbalances in embryonal rhabdomyosarcoma revealed by comparative genomic hybridization and fluorescence in situ hybridization: an intergroup rhabdomyosarcoma study. Genes Chromosomes Cancer. 2000;27:337-344.
4. Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatol Clin. 1995;13:113-125.
5. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, Vorechovsky I, Holmberg E, Unden AB, Gillies S, Negus K, Smyth I, Pressman C, et al. Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell. 1996;85:841-851.
6. Johnson RL, Rothman AL, Xie J, Goodrich LV, Bare JW, Bonifas JM, Quinn AG, Myers RM, Cox DR, Epstein EH Jr., Scott MP. Human homolog of patched, a candidate gene for the basal cell nevus syndrome. Science. 1996;272:1668-1671.
7. Hahn H, Wojnowski L, Zimmer AM, Hall J, Miller G, Zimmer A. Rhabdomyosarcomas and radiation hypersensitivity in a mouse model of Gorlin syndrome. Nat Med. 1998;4:619-622.
8. Ryan KE, Chiang C. Hedgehog secretion and signal transduction in vertebrates. J Biol Chem. 2012;287:17905-17913.
9. Eichberger T, Sander V, Schnidar H, Regl G, Kasper M, Schmid C, Plamberger S, Kaser A, Aberger F, Frischauf AM. Overlapping and distinct transcriptional regulator properties of the GLI1 and GLI2 oncogenes. Genomics. 2006;87:616-632.
10. Varjosalo M, Taipale J. Hedgehog: functions and mechanisms. Genes Dev. 2008;22:2454-2472.
11. Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V, Beermann F, Ruiz IAA. Melanomas require HEDGEHOG-GLI signaling regulated by interactions between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007;104:5895-5900.
12. Gruber Filbin M, Dabral SK, Pazyra-Murphy MF, Ramkissoon S, Kung AL, Pak E, Chung J, Theisen MA, Sun Y, Franchetti Y, Sun Y, Shulman DS, Redjal N, et al. Coordinate activation of Shh and PI3K signaling in PTENdeficient glioblastoma: new therapeutic opportunities. Nat Med. 2013;19:1518-1523.
13. Wang Y, Ding Q, Yen CJ, Xia W, Izzo JG, Lang JY, Li CW, Hsu JL, Miller SA, Wang X, Lee DF, Hsu JM, Huo L, et al. The crosstalk of mTOR/S6K1 and Hedgehog pathways. Cancer Cell. 2012;21:374-387.
14. Nolan-Stevaux O, Lau J, Truitt ML, Chu GC, Hebrok M, Fernandez-Zapico ME, Hanahan D. GLI1 is regulated through Smoothened-independent mechanisms in neoplastic pancreatic ducts and mediates PDAC cell survival and transformation. Genes Dev. 2009;23:24-36.
15. Seto M, Ohta M, Asaoka Y, Ikenoue T, Tada M, Miyabayashi K, Mohri D, Tanaka Y, Ijichi H, Tateishi K, Kanai F, Kawabe T, Omata M. Regulation of the hedgehog signaling by the mitogen-activated protein kinase cascade in gastric cancer. Mol Carcinog. 2009;48:703-712.
16. Wei L, Xu Z. Cross-signaling among phosphinositide-3 kinase, mitogen-activated protein kinase and sonic hedgehog pathways exists in esophageal cancer. Int J Cancer. 2011;129:275-284.
17. Ramaswamy B, Lu Y, Teng KY, Nuovo G, Li X, Shapiro CL, Majumder S. Hedgehog signaling is a novel therapeutic target in tamoxifen-resistant breast cancer aberrantly activated by PI3K/AKT pathway. Cancer Res. 2012;72:5048-5059.
18. Fulda S. Tumor resistance to apoptosis. Int J Cancer. 2009;124:511-515.
19. Fulda S, Debatin KM. Extrinsic versus intrinsic apoptosis pathways in anticancer chemotherapy. Oncogene. 2006;25:4798-4811.
20. Adams JM, Cory S. Bcl-2-regulated apoptosis: mechanism and therapeutic potential. Curr Opin Immunol. 2007;19:488-496.
21. Riedl SJ, Salvesen GS. The apoptosome: signalling platform of cell death. Nat Rev Mol Cell Biol. 2007;8:405-413.
22. Zibat A, Missiaglia E, Rosenberger A, Pritchard-Jones K, Shipley J, Hahn H, Fulda S. Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma. Oncogene. 2010;29:6323-6330.
23. Roberts WM, Douglass EC, Peiper SC, Houghton PJ, Look AT. Amplification of the gli gene in childhood sarcomas. Cancer Res. 1989;49:5407-5413.
24. Bridge JA, Liu J, Qualman SJ, Suijkerbuijk R, Wenger G, Zhang J, Wan X, Baker KS, Sorensen P, Barr FG. Genomic gains and losses are similar in genetic and histologic subsets of rhabdomyosarcoma, whereas amplification predominates in embryonal with anaplasia and alveolar subtypes. Genes Chromosomes Cancer. 2002;33:310-321.
25. Wertz IE, Kusam S, Lam C, Okamoto T, Sandoval W, Anderson DJ, Helgason E, Ernst JA, Eby M, Liu J, Belmont LD, Kaminker JS, O'Rourke KM, et al. Sensitivity to antitubulin chemotherapeutics is regulated by MCL1 and FBW7. Nature. 2011;471:110-114.
26. Hacker S, Dittrich A, Mohr A, Schweitzer T, Rutkowski S, Krauss J, Debatin KM, Fulda S. Histone deacetylase inhibitors cooperate with IFN-gamma to restore caspase-8 expression and overcome TRAIL resistance in cancers with silencing of caspase-8. Oncogene. 2009;28:3097-3110.
27. Yauch RL, Dijkgraaf GJ, Alicke B, Januario T, Ahn CP, Holcomb T, Pujara K, Stinson J, Callahan CA, Tang T, Bazan JF, Kan Z, Seshagiri S, et al. Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma. Science. 2009;326:572-574.
28. Grespi F, Soratroi C, Krumschnabel G, Sohm B, Ploner C, Geley S, Hengst L, Hacker G, Villunger A. BH3-only protein Bmf mediates apoptosis upon inhibition of CAPdependent protein synthesis. Cell Death Differ. 2010;17:1672-1683.
29. Beauchamp EM, Ringer L, Bulut G, Sajwan KP, Hall MD, Lee YC, Peaceman D, Ozdemirli M, Rodriguez O, Macdonald TJ, Albanese C, Toretsky JA, Uren A. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. J Clin Invest. 2011;121:148-160.
30. Kim J, Lee JJ, Kim J, Gardner D, Beachy PA. Arsenic antagonizes the Hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107:13432-13437.
31. Morales AA, Gutman D, Lee KP, Boise LH. BH3-only proteins Noxa, Bmf, and Bim are necessary for arsenic trioxide-induced cell death in myeloma. Blood. 2008;111:5152-5162.
32. Cain K, Bratton SB, Cohen GM. The Apaf-1 apoptosome:a large caspase-activating complex. Biochimie. 2002;84:203-214.
33. Zou H, Yang R, Hao J, Wang J, Sun C, Fesik SW, Wu JC, Tomaselli KJ, Armstrong RC. Regulation of the Apaf-1/ caspase-9 apoptosome by caspase-3 and XIAP. J Biol Chem. 2003;278:8091-8098.
34. Han Z, Hendrickson EA, Bremner TA, Wyche JH. A sequential two-step mechanism for the production of the mature p17:p12 form of caspase-3 in vitro. J Biol Chem. 1997;272:13432-13436.
35. Tostar U, Malm CJ, Meis-Kindblom JM, Kindblom LG, Toftgard R, Unden AB. Deregulation of the hedgehog signalling pathway: a possible role for the PTCH and SUFU genes in human rhabdomyoma and rhabdomyosarcoma development. J Pathol. 2006;208:17-25.
36. Calzada-Wack J, Schnitzbauer U, Walch A, Wurster KH, Kappler R, Nathrath M, Hahn H. Analysis of the PTCH coding region in human rhabdomyosarcoma. Hum Mutat. 2002;20:233-234.
37. Ragazzini P, Gamberi G, Pazzaglia L, Serra M, Magagnoli G, Ponticelli F, Ferrari C, Ghinelli C, Alberghini M, Bertoni F, Picci P, Benassi MS. Amplification of CDK4, MDM2, SAS and GLI genes in leiomyosarcoma, alveolar and embryonal rhabdomyosarcoma. Histol Histopathol. 2004;19:401-411.
38. Pressey JG, Anderson JR, Crossman DK, Lynch JC, Barr FG. Hedgehog pathway activity in pediatric embryonal rhabdomyosarcoma and undifferentiated sarcoma: a report from the Children's Oncology Group. Pediatr Blood Cancer. 2011;57:930-938.
39. Roberts WM, Douglass EC, Peiper SC, Houghton PJ, Look AT. Amplification of the gli gene in childhood sarcomas. Cancer Res. 1989;49:5407-5413.
40. Paulson V, Chandler G, Rakheja D, Galindo RL, Wilson K, Amatruda JF, Cameron S. High-resolution array CGH identifies common mechanisms that drive embryonal rhabdomyosarcoma pathogenesis. Genes Chromosomes Cancer. 2011;50:397-408.
41. Petricoin EF 3rd, Espina V, Araujo RP, Midura B, Yeung C, Wan X, Eichler GS, Johann DJ Jr, Qualman S, Tsokos M, Krishnan K, Helman LJ, Liotta LA. Phosphoprotein pathway mapping: Akt/mammalian target of rapamycin activation is negatively associated with childhood rhabdomyosarcoma survival. Cancer Res. 2007;67:3431-3440.
42. Tostar U, Toftgard R, Zaphiropoulos PG, Shimokawa T. Reduction of human embryonal rhabdomyosarcoma tumor growth by inhibition of the hedgehog signaling pathway. Genes Cancer. 2010;1:941-951.
43. Sekulic A, Migden MR, Oro AE, Dirix L, Lewis KD, Hainsworth JD, Solomon JA, Yoo S, Arron ST, Friedlander PA, Marmur E, Rudin CM, Chang AL, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012;366:2171-2179.
44. Kool M, Jones DT, Jager N, Northcott PA, Pugh TJ, Hovestadt V, Piro RM, Esparza LA, Markant SL, Remke M, Milde T, Bourdeaut F, Ryzhova M, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25:393-405.
45. Brechbiel J, Miller-Moslin K, Adjei AA. Crosstalk between hedgehog and other signaling pathways as a basis for combination therapies in cancer. Cancer Treat Rev. 2014;40:750-759.
46. Dijkgraaf GJ, Alicke B, Weinmann L, Januario T, West K, Modrusan Z, Burdick D, Goldsmith R, Robarge K, Sutherlin D, Scales SJ, Gould SE, Yauch RL, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011;71:435-444.
47. Buonamici S, Williams J, Morrissey M, Wang A, Guo R, Vattay A, Hsiao K, Yuan J, Green J, Ospina B, Yu Q, Ostrom L, Fordjour P, et al. Interfering with resistance to smoothened antagonists by inhibition of the PI3K pathway in medulloblastoma. Sci Transl Med. 2010;2:51ra70.
48. Tang Y, Gholamin S, Schubert S, Willardson MI, Lee A, Bandopadhayay P, Bergthold G, Masoud S, Nguyen B, Vue N, Balansay B, Yu F, Oh S, et al. Epigenetic targeting of Hedgehog pathway transcriptional output through BET bromodomain inhibition. Nat Med. 2014;20:732-740.
49. Robarge KD, Brunton SA, Castanedo GM, Cui Y, Dina MS, Goldsmith R, Gould SE, Guichert O, Gunzner JL, Halladay J, Jia W, Khojasteh C, Koehler MF, et al. GDC-0449-a potent inhibitor of the hedgehog pathway. Bioorg Med Chem Lett. 2009;19:5576-5581.
50. Raynaud FI, Eccles S, Clarke PA, Hayes A, Nutley B, Alix S, Henley A, Di-Stefano F, Ahmad Z, Guillard S, Bjerke LM, Kelland L, Valenti M, et al. Pharmacologic characterization of a potent inhibitor of class I phosphatidylinositide 3-kinases. Cancer Res. 2007;67:5840-5850.
51. Lauth M, Bergstrom A, Shimokawa T, Toftgard R. Inhibition of GLI-mediated transcription and tumor cell growth by small-molecule antagonists. Proc Natl Acad Sci U S A. 2007;104:8455-8460.
52. Fulda S, Sieverts H, Friesen C, Herr I, Debatin KM. The CD95 (APO-1/Fas) system mediates drug-induced apoptosis in neuroblastoma cells. Cancer Res. 1997;57:3823-3829.
53. Walter D, Satheesha S, Albrecht P, Bornhauser BC, D'Alessandro V, Oesch SM, Rehrauer H, Leuschner I, Koscielniak E, Gengler C, Moch H, Bernasconi M, Niggli FK, et al. CD133 positive embryonal rhabdomyosarcoma stemlike cell population is enriched in rhabdospheres. PLoS One. 2011;6:e19506.
54. Chou TC. The median-effect principle and the combination index for quantitation of synergism and antagonism. In:Chou TC, ed. Synergism and antagonism in chemotherapy. (San Diego, USA) Academic Press), 1991; pp. 61-102