Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells

eLife

Volumn 4, Issue AUGUST2015, 2015, Pages

  Korkut, Anil ^a   Wang, Weiqing ^a   Demir, Emek ^a   Aksoy, Bulent Arman ^a,b   Jing, Xiaohong ^a   Molinelli, Evan J ^a   Babur, Özgün ^a   Bemis, Debra L ^a   Sumer, Selcuk Onur ^a   Solit, David B ^a   Pratilas, Christine A ^c   Sander, Chris ^a  

^a MEMORIAL SLOAN KETTERING CANCER CENTER   (United States)

^b Memorial Sloan Kettering Cancer Center ^*  (United States)

^c JOHNS HOPKINS UNIVERSITY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

B RAF KINASE; BROMODOMAIN INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE; MYC PROTEIN; PHOSPHATIDYLETHANOLAMINE BINDING PROTEIN; PROTEIN KINASE B; PROTEIN KINASE INHIBITOR; ANTINEOPLASTIC AGENT; DRUG COMBINATION; RAF PROTEIN;

ALGORITHM; ARTICLE; CELL VIABILITY; COMPUTER MODEL; COMPUTER SIMULATION; CONTROLLED STUDY; COST; DNA FINGERPRINTING; ENZYME ACTIVITY; GENE TRANSFER; HUMAN; HUMAN CELL; MATHEMATICAL COMPUTING; MELANOMA CELL; PHENOTYPE; POLYMERASE CHAIN REACTION; PROTEIN MICROARRAY; PROTEIN PROTEIN INTERACTION; PROTEOMICS; SIGNAL TRANSDUCTION; ANTAGONISTS AND INHIBITORS; BIOLOGICAL MODEL; BIOLOGY; CYTOLOGY; DRUG COMBINATION; DRUG RESISTANCE; GENE REGULATORY NETWORK; MELANOMA; PROCEDURES; THEORETICAL MODEL; TUMOR CELL LINE;

ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; COMPUTATIONAL BIOLOGY; CYTOLOGICAL TECHNIQUES; DRUG COMBINATIONS; DRUG RESISTANCE; GENE REGULATORY NETWORKS; HUMANS; MELANOMA; MODELS, BIOLOGICAL; MODELS, THEORETICAL; RAF KINASES;

EID: 84940527513     PISSN: None     EISSN: 2050084X     Source Type: Journal    
DOI: 10.7554/eLife.04640     Document Type: Article

References (68)

1. Anastas JN, Kulikauskas RM, Tamir T, Rizos H, Long GV, von Euw EM, Yang PT, Chen HW, Haydu L, Toroni RA, Lucero OM, Chien AJ, Moon RT. 2014. WNT5A enhances resistance of melanoma cells to targeted BRAF inhibitors. The Journal of Clinical Investigation 124:2877-2890. doi: 10.1172/JCI70156.
2. Bader GD, Cary MP, Sander C. 2006. Pathguide: a pathway resource list. Nucleic Acids Research 34:D504-D506. doi: 10.1093/nar/gkj126.
3. Bender C, von der Heyde S, Henjes F, Wiemann S, Korf U, Beissbarth T. 2011. Inferring signalling networks from longitudinal data using sampling based approaches in the R-package 'ddepn'. BMC Bioinformatics 12:291. doi: 10.1186/1471-2105-12-291.
4. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, Spevak W, Zhang C, Zhang Y, Habets G, Burton EA, Wong B, Tsang G, West BL, Powell B, Shellooe R, Marimuthu A, Nguyen H, Zhang KY, Artis DR, Schlessinger J, Su F, Higgins B, Iyer R, D'Andrea K, Koehler A, Stumm M, Lin PS, Lee RJ, Grippo J, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, Chapman PB, Flaherty KT, Xu X, Nathanson KL, Nolop K. 2010. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 467:596-599. doi: 10.1038/ nature09454.
5. Breitkreutz A, Choi H, Sharom JR, Boucher L, Neduva V, Larsen B, Lin ZY, Breitkreutz BJ, Stark C, Liu G, Ahn J, Dewar-Darch D, Reguly T, Tang X, Almeida R, Qin ZS, Pawson T, Gingras AC, Nesvizhskii AI, Tyers M. 2010. A global protein kinase and phosphatase interaction network in yeast. Science 328:1043-1046. doi: 10.1126/ science.1176495.
6. Cerami EG, Gross BE, Demir E, Rodchenkov I, Babur O, Anwar N, Schultz N, Bader GD, Sander C. 2011. Pathway commons, a web resource for biological pathway data. Nucleic Acids Research 39:D685-D690. doi: 10.1093/nar/ gkq1039.
7. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, Dummer R, Garbe C, Testori A, Maio M, Hogg D, Lorigan P, Lebbe C, Jouary T, Schadendorf D, Ribas A, O'Day SJ, Sosman JA, Kirkwood JM, Eggermont AM, Dreno B, Nolop K, Li J, Nelson B, Hou J, Lee RJ, Flaherty KT, McArthur GA, BRIM-3 Study Group. 2011. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. The New England Journal of Medicine 364:2507-2516. doi: 10.1056/NEJMoa1103782.
8. Chen WW, Schoeberl B, Jasper PJ, Niepel M, Nielsen UB, Lauffenburger DA, Sorger PK. 2009. Input-output behavior of ErbB signaling pathways as revealed by a mass action model trained against dynamic data. Molecular Systems Biology 5:239. doi: 10.1038/msb.2008.74.
9. Choi S, Henderson MJ, Kwan E, Beesley AH, Sutton R, Bahar AY, Giles J, Venn NC, Pozza LD, Baker DL, Marshall GM, Kees UR, Haber M, Norris MD. 2007. Relapse in children with acute lymphoblastic leukemia involving selection of a preexisting drug-resistant subclone. Blood 110:632-639. doi: 10.1182/blood-2007-01-067785.
10. Ciriello G, Miller ML, Aksoy BA, Senbabaoglu Y, Schultz N, Sander C. 2013. Emerging landscape of oncogenic signatures across human cancers. Nature Genetics 45:1127-1133. doi: 10.1038/ng.2762.
11. Clegg NJ, Wongvipat J, Joseph JD, Tran C, Ouk S, Dilhas A, Chen Y, Grillot K, Bischoff ED, Cai L, Aparicio A, Dorow S, Arora V, Shao G, Qian J, Zhao H, Yang G, Cao C, Sensintaffar J, Wasielewska T, Herbert MR, Bonnefous C, Darimont B, Scher HI, Smith-Jones P, Klang M, Smith ND, De Stanchina E, Wu N, Ouerfelli O, Rix PJ, Heyman RA, Jung ME, Sawyers CL, Hager JH. 2012. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Research 72:1494-1503. doi: 10.1158/0008-5472.CAN-11-3948.
12. Dang CV. 2012. MYC on the path to cancer. Cell 149:22-35. doi: 10.1016/j.cell.2012.03.003.
13. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, Teague J, Woffendin H, Garnett MJ, Bottomley W, Davis N, Dicks E, Ewing R, Floyd Y, Gray K, Hall S, Hawes R, Hughes J, Kosmidou V, Menzies A, Mould C, Parker A, Stevens C, Watt S, Hooper S, Wilson R, Jayatilake H, Gusterson BA, Cooper C, Shipley J, Hargrave D, Pritchard-Jones K, Maitland N, Chenevix-Trench G, Riggins GJ, Bigner DD, Palmieri G, Cossu A, Flanagan A, Nicholson A, Ho JW, Leung SY, Yuen ST, Weber BL, Seigler HF, Darrow TL, Paterson H, Marais R, Marshall CJ, Wooster R, Stratton MR, Futreal PA. 2002. Mutations of the BRAF gene in human cancer. Nature 417:949-954. doi: 10.1038/nature00766.
14. Dawson MA, Prinjha RK, Dittmann A, Giotopoulos G, Bantscheff M, Chan WI, Robson SC, Chung CW, Hopf C, Savitski MM, Huthmacher C, Gudgin E, Lugo D, Beinke S, Chapman TD, Roberts EJ, Soden PE, Auger KR, Mirguet O, Doehner K, Delwel R, Burnett AK, Jeffrey P, Drewes G, Lee K, Huntly BJ, Kouzarides T. 2011. Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukaemia. Nature 478: 529-533. doi: 10.1038/nature10509.
15. Delmore JE, Issa GC, Lemieux ME, Rahl PB, Shi J, Jacobs HM, Kastritis E, Gilpatrick T, Paranal RM, 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. 2011. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell 146:904-917. doi: 10.1016/j.cell.2011.08.017.
16. Demir E, Cary MP, Paley S, Fukuda K, Lemer C, Vastrik I, Wu GN, D'Eustachio P, Schaefer C, Luciano J, Schacherer F, Martinez-Flores I, Hu Z, Jimenez-Jacinto V, Joshi-Tope G, Kandasamy K, Lopez-Fuentes AC, Mi H, Pichler E, Rodchenkov I, Splendiani A, Tkachev S, Zucker J, Gopinath G, Rajasimha H, Ramakrishnan R, Shah I, Syed M, Anwar N, Babur O, Blinov M, Brauner E, Corwin D, Donaldson S, Gibbons F, Goldberg R, Hornbeck P, Luna A, Murray-Rust P, Neumann E, Ruebenacker O, Samwald M, van Iersel M, Wimalaratne S, Allen K, Braun B, Whirl-Carrillo M, Cheung KH, Dahlquist K, Finney A, Gillespie M, Glass E, Gong L, Haw R, Honig M, Hubaut O, Kane D, Krupa S, Kutmon M, Leonard J, Marks D, Merberg D, Petri V, Pico A, Ravenscroft D, Ren L, Shah N, Sunshine M, Tang R, Whaley R, Letovksy S, Buetow KH, Rzhetsky A, Schachter V, Sobral BS, Dogrusoz U, McWeeney S, Aladjem M, Birney E, Collado-Vides J, Goto S, Hucka M, Le Novère N, Maltsev N, Pandey A, Thomas P, Wingender E, Karp PD, Sander C, Bader GD. 2010. The BioPAX community standard for pathway data sharing. Nature Biotechnology 28:935-942. doi: 10.1038/nbt.1666.
17. Dogrusoz U, Cetintas A, Demir E, Babur O. 2009. Algorithms for effective querying of compound graph-based pathway databases. BMC Bioinformatics 10:376. doi: 10.1186/1471-2105-10-376.
18. Domcke S, Sinha R, Levine DA, Sander C, Schultz N. 2013. Evaluating cell lines as tumour models by comparison of genomic profiles. Nature Communications 4:2126. doi: 10.1038/ncomms3126.
19. Filippakopoulos P, Knapp S. 2014. Targeting bromodomains: epigenetic readers of lysine acetylation. Nature Reviews. Drug Discovery 13:337-356. doi: 10.1038/nrd4286.
20. Fiskus W, Sharma S, Qi J, Shah B, Devaraj SG, Leveque C, Portier BP, Iyer S, Bradner JE, Bhalla KN. 2014. BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD. Molecular Cancer Therapeutics 13:2315-2327. doi: 10.1158/1535-7163.MCT-14-0258.
21. Fitzgerald JB, Schoeberl B, Nielsen UB, Sorger PK. 2006. Systems biology and combination therapy in the quest for clinical efficacy. Nature Chemical Biology 2:458-466. doi: 10.1038/nchembio817.
22. Flaherty KT, Infante JR, Daud A, Gonzalez R, Kefford RF, Sosman J, Hamid O, Schuchter L, Cebon J, Ibrahim N, Kudchadkar R, Burris HA III, Falchook G, Algazi A, Lewis K, Long GV, Puzanov I, Lebowitz P, Singh A, Little S, Sun P, Allred A, Ouellet D, Kim KB, Patel K, Weber J. 2012a. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. New England Journal of Medicine 367:1694-1703. doi: 10.1056/NEJMoa1210093.
23. Flaherty KT, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, Demidov LV, Hassel JC, Rutkowski P, Mohr P, Dummer R, Trefzer U, Larkin JM, Utikal J, Dreno B, Nyakas M, Middleton MR, Becker JC, Casey M, Sherman LJ, Wu FS, Ouellet D, Martin AM, Patel K, Schadendorf D, METRIC Study Group. 2012b. Improved survival with MEK inhibition in BRAFmutated melanoma. The New England Journal of Medicine 367:107-114. doi: 10.1056/NEJMoa1203421.
24. Garraway LA, Janne PA. 2012. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discovery 2:214-226. doi: 10.1158/2159-8290.CD-12-0012.
25. Haluska FG, Tsao H, Wu H, Haluska FS, Lazar A, Goel V. 2006. Genetic alterations in signaling pathways in melanoma. Clinical Cancer Research 12:2301s-2307s. doi: 10.1158/1078-0432.CCR-05-2518.
26. Hindmarsh AC. 1993. ODEPACK, a systematized collection of ODE solvers. In: Stepleman RS, Carver M, Peskin R, Ames WF, Vichnevetsky R, editors. Scientific Computing. Amsterdam: North-Holland Publishing Company. p. 55-64.
27. Huang C, Park CC, Hilsenbeck SG, Ward R, Rimawi MF, Wang YC, Shou J, Bissell MJ, Osborne CK, Schiff R. 2011. beta1 integrin mediates an alternative survival pathway in breast cancer cells resistant to lapatinib. Breast Cancer Research 13:R84. doi: 10.1186/bcr2936.
28. Jaynes ET. 1957. Information theory and statistical mechanics. Physical Review 106:620-630. doi: 10.1103/ PhysRev.106.620.
29. Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, Johnson LA, Emery CM, Stransky N, Cogdill AP, Barretina J, Caponigro G, Hieronymus H, Murray RR, Salehi-Ashtiani K, Hill DE, Vidal M, Zhao JJ, Yang X, Alkan O, Kim S, Harris JL, Wilson CJ, Myer VE, Finan PM, Root DE, Roberts TM, Golub T, Flaherty KT, Dummer R, Weber BL, Sellers WR, Schlegel R, Wargo JA, Hahn WC, Garraway LA. 2010. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468:968-972. doi: 10.1038/nature09627.
30. Klinger B, Sieber A, Fritsche-Guenther R, Witzel F, Berry L, Schumacher D, Yan YB, Durek P, Merchant M, Schafer R, Sers C, Blüthgen N. 2013. Network quantification of EGFR signaling unveils potential for targeted combination therapy. Molecular Systems Biology 9:673. doi: 10.1038/msb.2013.29.
31. Le Novere N, Hucka M, Mi H, Moodie S, Schreiber F, Sorokin A, Demir E, Wegner K, Aladjem MI, Wimalaratne SM, Bergman FT, Gauges R, Ghazal P, Kawaji H, Li L, Matsuoka Y, Villé ger A, Boyd SE, Calzone L, Courtot M, Dogrusoz U, Freeman TC, Funahashi A, Ghosh S, Jouraku A, Kim S, Kolpakov F, Luna A, Sahle S, Schmidt E, Watterson S, Wu G, Goryanin I, Kell DB, Sander C, Sauro H, Snoep JL, Kohn K, Kitano H. 2009. The systems biology graphical notation. Nature Biotechnology 27:735-741. doi: 10.1038/nbt.1558.
32. Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, Huang A, Wong WL, Callahan MK, Merghoub T, Wolchok JD, de Stanchina E, Chandarlapaty S, Poulikakos PI, Fagin JA, Rosen N. 2012. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas. Cancer Cell 22:668-682. doi: 10.1016/j.ccr.2012.10.009.
33. Lockwood WW, Zejnullahu K, Bradner JE, Varmus H. 2012. Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins. Proceedings of the National Academy of Sciences of USA 109:19408-19413. doi: 10.1073/pnas.1216363109.
34. Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C,Mandalà M,MillwardM, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. 2014. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. The New England Journal of Medicine 371:1877-1888. doi: 10.1056/NEJMoa1406037.
35. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, Bradner JE, Lee TI, Young RA. 2013. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell 153:320-334. doi: 10.1016/j.cell.2013.03.036.
36. Matthews L, Gopinath G, Gillespie M, Caudy M, Croft D, de Bono B, Garapati P, Hemish J, Hermjakob H, Jassal B, Gopinath GR, Wu GR, Matthews L, Lewis S, Birney E, Stein L. 2009. Reactome knowledgebase of human biological pathways and processes. Nucleic Acids Research 37:D619-D622. doi: 10.1093/nar/gkn863.
37. Mertz JA, Conery AR, Bryant BM, Sandy P, Balasubramanian S, Mele DA, Bergeron L, Sims RJ III. 2011. Targeting MYC dependence in cancer by inhibiting BET bromodomains. Proceedings of the National Academy of Sciences of USA 108:16669-16674. doi: 10.1073/pnas.1108190108.
38. Miller ML, Molinelli EJ, Nair JS, Sheikh T, Samy R, Jing X, He Q, Korkut A, Crago AM, Singer S, Schwartz GK, Sander C. 2013. Drug synergy screen and network modeling in dedifferentiated liposarcoma identifies CDK4 and IGF1R as synergistic drug targets. Science Signaling 6:ra85. doi: 10.1126/scisignal.2004014.
39. Molinelli EJ, Korkut A, Wang W, Miller ML, Gauthier NP, Jing X, Kaushik P, He Q, Mills G, Solit DB, Pratilas CA, Weigt M, Braunstein A, Pagnani A, Zecchina R, Sander C. 2013. Perturbation biology: inferring signaling networks in cellular systems. PLOS Computational Biology 9:e1003290. doi: 10.1371/journal.pcbi.1003290.
40. Montanari A, Ricci-Tersenghi F, Semerjian G. 2007. Solving constraint satisfaction problems through belief propagation-guided decimation. arXiv, 0709.1667. http://arxiv.org/abs/0709.1667.
41. Nazarian R, Shi H, Wang Q, Kong X, Koya RC, Lee H, Chen Z, Lee MK, Attar N, Sazegar H, Chodon T, Nelson SF, McArthur G, Sosman JA, Ribas A, Lo RS. 2010. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 468:973-977. doi: 10.1038/nature09626.
42. Neeley ES, Kornblau SM, Coombes KR, Baggerly KA. 2009. Variable slope normalization of reverse phase protein arrays. Bioinformatics 25:1384-1389. doi: 10.1093/bioinformatics/btp174.
43. Nelander S, Wang W, Nilsson B, She QB, Pratilas C, Rosen N, Gennemark P, Sander C. 2008. Models from experiments: combinatorial drug perturbations of cancer cells. Molecular Systems Biology 4:216. doi: 10.1038/ msb.2008.53.
44. Nusse M, Kramer J. 1984. Flow cytometric analysis of micronuclei found in cells after irradiation. Cytometry 5: 20-25. doi: 10.1002/cyto.990050105.
45. O'Reilly KE, Rojo F, She QB, Solit D, Mills GB, Smith D, Lane H, Hofmann F, Hicklin DJ, Ludwig DL, Baselga J, Rosen N. 2006. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Research 66:1500-1508. doi: 10.1158/0008-5472.CAN-05-2925.
46. Oates CJ, Dondelinger F, Bayani N, Korkola J, Gray JW, Mukherjee S. 2014. Causal network inference using biochemical kinetics. Bioinformatics 30:I468-I474. doi: 10.1093/bioinformatics/btu452.
47. Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. 2005. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLOS Medicine 2:225-235. doi: 10.1371/journal.pmed.0020073.
48. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. 2010. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 464:427-430. doi: 10.1038/nature08902.
49. Prahallad A, Sun C, Huang S, Di Nicolantonio F, Salazar R, Zecchin D, Beijersbergen RL, Bardelli A, Bernards R. 2012. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 483:100-103. doi: 10.1038/nature10868.
50. Pratilas CA, Taylor BS, Ye Q, Viale A, Sander C, Solit DB, Rosen N. 2009. (V600E)BRAF is associated with disabled feedback inhibition of RAF-MEK signaling and elevated transcriptional output of the pathway. Proceedings of the National Academy of Sciences of USA 106:4519-4524. doi: 10.1073/pnas.0900780106.
51. Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, Nekritz EA, Zeid R, Gustafson WC, Greninger P, Garnett MJ, McDermott U, Benes CH, Kung AL, Weiss WA, Bradner JE, Stegmaier K. 2013. Targeting MYCN in neuroblastoma by BET bromodomain inhibition. Cancer Discovery 3:308-323. doi: 10.1158/2159-8290.CD-12-0418.
52. Rother J, Jones D. 2009. Molecular markers of tumor progression in melanoma. Current genomics 10:231-239. doi: 10.2174/138920209788488526.
53. Saez-Rodriguez J, Alexopoulos LG, Epperlein J, Samaga R, Lauffenburger DA, Klamt S, Sorger PK. 2009. Discrete logic modelling as a means to link protein signalling networks with functional analysis of mammalian signal transduction. Molecular Systems Biology 5:331. doi: 10.1038/msb.2009.87.
54. Saez-Rodriguez J, Alexopoulos LG, Zhang MS, Morris MK, Lauffenburger DA, Sorger PK. 2011. Comparing signaling networks between normal and transformed hepatocytes using discrete logical models. Cancer Research 71:5400-5411. doi: 10.1158/0008-5472.CAN-10-4453.
55. Schaefer CF, Anthony K, Krupa S, Buchoff J, Day M, Hannay T, Buetow KH. 2009. PID: the pathway interaction database. Nucleic Acids Research 37:D674-D679. doi: 10.1093/nar/gkn653.
56. Schafer J, Strimmer K. 2005. A shrinkage approach to large-scale covariance matrix estimation and implications for functional genomics. Statistical Applications in Genetics and Molecular Biology 4:Article32. doi: 10.2202/1544-6115.1175.
57. Segura MF, Fontanals-Cirera B, Gaziel-Sovran A, Guijarro MV, Hanniford D, Zhang GT, Gonzalez-Gomez P, Morante M, Jubierre L, Zhang WJ, Darvishian F, Ohlmeyer M, Osman I, Zhou MM, Hernando E. 2013. BRD4 sustains melanoma proliferation and represents a new target for epigenetic therapy. Cancer Research 73: 6264-6276. doi: 10.1158/0008-5472.CAN-13-0122-T.
58. Selbach M, Mann M. 2006. Protein interaction screening by quantitative immunoprecipitation combined with knockdown (QUICK). Nature Methods 3:981-983. doi: 10.1038/nmeth972.
59. Solit DB, Garraway LA, Pratilas CA, Sawai A, Getz G, Basso A, Ye Q, Lobo JM, She Y, Osman I, Golub TR, Sebolt-Leopold J, Sellers WR, Rosen N. 2006. BRAF mutation predicts sensitivity to MEK inhibition. Nature 439: 358-362. doi: 10.1038/nature04304.
60. Sosman JA, Kim KB, Schuchter L, Gonzalez R, Pavlick AC, Weber JS, McArthur GA, Hutson TE, Moschos SJ, Flaherty KT, Hersey P, Kefford R, Lawrence D, Puzanov I, Lewis KD, Amaravadi RK, Chmielowski B, Lawrence HJ, Shyr Y, Ye F, Li J, Nolop KB, Lee RJ, Joe AK, Ribas A. 2012. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. The New England Journal of Medicine 366:707-714. doi: 10.1056/NEJMoa1112302.
61. Soucek L, Whitfield J, Martins CP, Finch AJ, Murphy DJ, Sodir NM, Karnezis AN, Swigart LB, Nasi S, Evan GI. 2008. Modelling Myc inhibition as a cancer therapy. Nature 455:679-683. doi: 10.1038/nature07260.
62. Sun C, Wang L, Huang S, Heynen GJ, Prahallad A, Robert C, Haanen J, Blank C, Wesseling J, Willems SM, Zecchin D, Hobor S, Bajpe PK, Lieftink C, Mateus C, Vagner S, Grernrum W, Hofland I, Schlicker A, Wessels LF, Beijersbergen RL, Bardelli A, Di Nicolantonio F, Eggermont AM, Bernards R. 2014. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 508:118-122. doi: 10.1038/nature13121.
63. Tibes R, Qiu Y, Lu Y, Hennessy B, Andreeff M, Mills GB, Kornblau SM. 2006. Reverse phase protein array: validation of a novel proteomic technology and utility for analysis of primary leukemia specimens and hematopoietic stem cells. Molecular Cancer Therapeutics 5:2512-2521. doi: 10.1158/1535-7163.MCT-06-0334.
64. Van Allen EM, Wagle N, Sucker A, Treacy DJ, Johannessen CM, Goetz EM, Place CS, Taylor-Weiner A, Whittaker S, Kryukov GV, Hodis E, Rosenberg M, McKenna A, Cibulskis K, Farlow D, Zimmer L, Hillen U, Gutzmer R, Goldinger SM, Ugurel S, Gogas HJ, Egberts F, Berking C, Trefzer U, Loquai C, Weide B, Hassel JC, Gabriel SB, Carter SL, Getz G, Garraway LA, Schadendorf D, Dermatologic Cooperative Oncology Group of Germany (DeCOG). 2014. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discovery 4:94-109. doi: 10.1158/2159-8290.CD-13-0617.
65. Villanueva J, Vultur A, Lee JT, Somasundaram R, Fukunaga-Kalabis M, Cipolla AK, Wubbenhorst B, Xu X, Gimotty PA, Kee D, Santiago-Walker AE, Letrero R, D'Andrea K, Pushparajan A, Hayden JE, Brown KD, Laquerre S, McArthur GA, Sosman JA, Nathanson KL, Herlyn M. 2010. Acquired resistance to BRAF inhibitors mediated by a RAF kinase switch in melanoma can be overcome by cotargeting MEK and IGF-1R/PI3K. Cancer Cell 18: 683-695. doi: 10.1016/j.ccr.2010.11.023.
66. Wagle N, Van Allen EM, Treacy DJ, Frederick DT, Cooper ZA, Taylor-Weiner A, Rosenberg M, Goetz EM, Sullivan RJ, Farlow DN, Friedrich DC, Anderka K, Perrin D, Johannessen CM, McKenna A, Cibulskis K, Kryukov G, Hodis E, Lawrence DP, Fisher S, Getz G, Gabriel SB, Carter SL, Flaherty KT, Wargo JA, Garraway LA. 2013. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discovery 4:61-68. doi: 10.1158/2159-8290.CD-13-0631.
67. Xing F, Persaud Y, Pratilas CA, Taylor BS, Janakiraman M, She QB, Gallardo H, Liu C, Merghoub T, Hefter B, Dolgalev I, Viale A, Heguy A, De Stanchina E, Cobrinik D, Bollag G, Wolchok J, Houghton A, Solit DB. 2012. Concurrent loss of the PTEN and RB1 tumor suppressors attenuates RAF dependence in melanomas harboring (V600E)BRAF. Oncogene 31:446-457. doi: 10.1038/onc.2011.250.
68. Zhao B, Hemann MT, Lauffenburger DA. 2014. Intratumor heterogeneity alters most effective drugs in designed combinations. Proceedings of the National Academy of Sciences of USA 111:10773-10778. doi: 10.1073/pnas. 1323934111.