Oncogenic BRAF deletions that function as homodimers and are sensitive to inhibition by RAF dimer inhibitor LY3009120

Cancer Discovery

Volumn 6, Issue 3, 2016, Pages 300-315

  Chen, Shih Hsun ^a   Zhang, Youyan ^a   van Horn, Robert D ^a   Yin, Tinggui ^a   Buchanan, Sean ^a   Yadav, Vipin ^a   Mochalkin, Igor ^a   Wong, Swee Seong ^a   Yue, Yong Gang ^a   Huber, Lysiane ^a   Conti, Ilaria ^a   Henry, James R ^a   Starling, James J ^a   Plowman, Gregory D ^a   Peng, Sheng Bin ^a  

^a ELI LILLY AND COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ANTINEOPLASTIC AGENT; B RAF KINASE; DABRAFENIB; HOMODIMER; LY 3009120; UNCLASSIFIED DRUG; VEMURAFENIB; CARBANILAMIDE DERIVATIVE; LY3009120; PROTEIN KINASE INHIBITOR; PYRIMIDINE DERIVATIVE;

ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; CELL CYCLE ASSAY; CELL PROLIFERATION; CONTROLLED STUDY; DOWNSTREAM PROCESSING; FEMALE; GENE DELETION; GENE SILENCING; HUMAN; HUMAN CELL; IMMUNOPRECIPITATION; MICROSCOPY; NONHUMAN; PANCREAS CANCER; PHOSPHORYLATION; POLYMERASE CHAIN REACTION; PROTEIN EXPRESSION; RAT; SEQUENCE ANALYSIS; SIGNAL TRANSDUCTION; TUMOR GROWTH; TUMOR XENOGRAFT; WESTERN BLOTTING; ANIMAL; ANTAGONISTS AND INHIBITORS; CELL TRANSFORMATION; CHEMISTRY; DISEASE MODEL; DRUG RESISTANCE; DRUG SCREENING; ECTOPIC EXPRESSION; GENE EXPRESSION; GENETICS; MOLECULAR MODEL; MOUSE; PROTEIN CONFORMATION; PROTEIN DOMAIN; PROTEIN MULTIMERIZATION; TUMOR CELL LINE;

ANIMALS; ANTINEOPLASTIC AGENTS; CELL LINE, TUMOR; CELL TRANSFORMATION, NEOPLASTIC; DISEASE MODELS, ANIMAL; DRUG RESISTANCE, NEOPLASM; ECTOPIC GENE EXPRESSION; GENE DELETION; GENE EXPRESSION; HUMANS; MAP KINASE SIGNALING SYSTEM; MICE; MODELS, MOLECULAR; PHENYLUREA COMPOUNDS; PROTEIN CONFORMATION; PROTEIN INTERACTION DOMAINS AND MOTIFS; PROTEIN KINASE INHIBITORS; PROTEIN MULTIMERIZATION; PROTO-ONCOGENE PROTEINS B-RAF; PYRIMIDINES; XENOGRAFT MODEL ANTITUMOR ASSAYS;

EID: 84960131814     PISSN: 21598274     EISSN: 21598290     Source Type: Journal    
DOI: 10.1158/2159-8290.CD-15-0896     Document Type: Article

References (48)

1. Davies H, Bignell GR, Cox C, Stephens P, Edkins S, Clegg S, et al. Mutations of the BRAF gene in human cancer. Nature 2002; 417: 949-54
2. Wan PTC, Garnett MJ, Roe SM, Lee S, Niculescu-Duvaz D, Good VM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004; 116: 855-67
3. Lito P, Pratilas CA, Joseph EW, Tadi M, Halilovic E, Zubrowski M, et al. Relief of profound feedback inhibition of mitogenic signaling by RAF inhibitors attenuates their activity in BRAFV600E melanomas . Cancer Cell 2012; 22: 668-82
4. Lito P, Rosen N, Solit DB. Tumor adaptation and resistance to RAF inhibitors. Nat Med 2013; 19: 1401-9
5. Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, Moriceau G, et al. RAF inhibitor resistance is mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011; 480: 387-90
6. Tiacci E, Schiavoni G, Martelli MP, Boveri E, Pacini R, Tabarrini A, et al. Constant activation of the RAF-MEK-ERK pathway as a diagnostic and therapeutic target in hairy cell leukemia. Haematologica 2013; 98: 635-9
7. Badalian-Very G, Vergilio JA, Degar BA, MacConaill LE, Brandner B, Calicchio ML, et al. Recurrent BRAF mutations in Langerhans cell histiocytosis. Blood 2010; 116: 1919-23
8. Wellbrock C, Karasarides M, Marais R. The RAF proteins take centre stage. Nat Rev Mol Cell Biol 2004; 5: 875-85
9. Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacol Ther 2014; 142: 176-82
10. Garnett MJ, Marais R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 2004; 6: 313-9
11. Greaves WO, Verma S, Patel KP, Davies MA, Barkoh BA, Galbincea JM, et al. Frequency and spectrum of BRAF mutations in a retrospective, single-institution study of 1112 cases of melanoma. J Mol Diagn 2013; 15: 220-6
12. Yuen ST, Davies H, Chan TL, Ho JW, Bignell GR, Cox C, et al. Similarity of the phenotypic patterns associated with BRAF and KRAS mutations in colorectal neoplasia. Cancer Res 2002; 62: 6451-5
13. Lawrence MS, Stojanov P, Mermel CH, Robinson JT, Garraway LA, Golub TR, et al. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature 2014; 505: 495-501
14. Hutchinson KE, Lipson D, Stephens PJ, Otto G, Lehmann BD, Lyle PL, et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clin Cancer Res 2013; 19: 6696-702
15. Palanisamy N, Ateeq B, Kalyana-Sundaram S, Pfl ueger D, Ramnarayanan K, Shankar S, et al. Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 2010; 16: 793-8
16. Lee NV, Lira ME, Pavlicek A, Ye J, Buckman D, Bagrodia S, et al. A novel SND1-BRAF fusion confers resistance to c-Met inhibitor PF-04217903 in GTL16 cells through [corrected] MAPK activation. PLoS One 2012; 7: e39653
17. Ciampi R, Knauf JA, Kerler R, Gandhi M, Zhu Z, Nikiforova MN, et al. Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer. J Clin Invest 2005; 115: 94-101
18. Jones DT, Kocialkowski S, Liu L, Pearson DM, Backlund LM, Ichimura K, et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res 2008; 68: 8673-7
19. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun 2014; 5: 4846
20. Andreadi C, Cheung LK, Giblett S, Patel B, Jin H, Mercer K, et al. The intermediate-activity (L597V)BRAF mutant acts as an epistatic modifier of oncogenic RAS by enhancing signaling through the RAF/ MEK/ERK pathway. Genes Dev 2012; 26: 1945-58
21. Ikenoue T, Hikiba Y, Kanai F, Tanaka Y, Imamura J, Imamura T, et al. Functional analysis of mutations within the kinase activation segment of B-Raf in human colorectal tumors. Cancer Res 2003; 63: 8132-7
22. Roring M, Herr R, Fiala GJ, Heilmann K, Braun S, Eisenhardt AE, et al. Distinct requirement for an intact dimer interface in wild-type, V600E and kinase-dead B-Raf signalling. EMBO J 2012; 31: 2629-47
23. Yao Z, Torres NM, Tao A, Gao Y, Luo L, Li Q, et al. BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition. Cancer Cell 2015; 28: 370-83
24. Wellbrock C, Ogilvie L, Hedley D, Karasarides M, Martin J, Niculescu-Duvaz D, et al. V599EB-RAF is an oncogene in melanocytes. Cancer Res 2004; 64: 2338-42
25. Yang H, Higgins B, Kolinsky K, Packman K, Go Z, Iyer R, et al. RG7204 (PLX4032), a selective BRAFV600E inhibitor, displays potent antitumor activity in preclinical melanoma models. Cancer Res 2010; 70: 5518-27
26. Bollag G, Hirth P, Tsai J, Zhang J, Ibrahim PN, Cho H, et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAFmutant melanoma. Nature 2010; 467: 596-9
27. King AJ, Arnone MR, Bleam MR, Moss KG, Yang J, Fedorowicz KE, et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One 2013; 8: e67583
28. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med 2010; 363: 809-19
29. Chapman PB, Hauschild A, Robert C, Haanen JB, Ascierto P, Larkin J, et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 2011; 364: 2507-16
30. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 2012; 380: 358-65
31. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010; 140: 209-21
32. Poulikakos PI, Zhang C, Bollag G, Shokat KM, Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wildtype BRAF. Nature 2010; 464: 427-30
33. Hatzivassiliou G, Song K, Yen I, Brandhuber BJ, Anderson DJ, Alvarado R, et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010; 464: 431-5
34. Sanchez-Laorden B, Viros A, Girotti MR, Pedersen M, Saturno G, Zambon A, et al. BRAF inhibitors induce metastasis in RAS mutant or inhibitor-resistant melanoma cells by reactivating MEK and ERK signaling. Sci Signal 2014; 7: ra30
35. H enry J R, K aufman M D, P eng S B, A hn Y M, C aldwell T M, V ogeti L, et al. Discovery of 1-(3,3-Dimethylbutyl)-3-(2-fl uoro-4-methyl-5-(7- methyl-2-(methylamino)pyrido[2,3-d]pyrimidin-6-yl)phenyl)urea (LY3009120) as a Pan-RAF inhibitor with minimal paradoxical activation and activity against BRAF or RAS mutant tumor cells. J Med Chem 2015; 58: 4165-79
36. Peng SB, Henry JR, Kaufman M, Lu WP, Smith B, Vogeti S, et al. Inhibition of RAF isoforms and active dimers by LY3009120 leads to anti-tumor activities in RAS or BRAF mutant cancers. Cancer Cell 2015; 28: 384-98
37. Fichter CD, Timme S, Braun JA, Gudernatsch V, Schopfl in A, Bogatyreva L, et al. EGFR, HER2 and HER3 dimerization patterns guide targeted inhibition in two histotypes of esophageal cancer. Int J Cancer 2014; 135: 1517-30
38. Freeman AK, Ritt DA, Morrison DK. Effects of Raf dimerization and its inhibition on normal and disease-associated Raf signaling. Mol Cell 2013; 49: 751-8
39. Rajakulendran T, Sahmi M, Lefrancois M, Sicheri F, Therrien M. A dimerization-dependent mechanism drives RAF catalytic activation. Nature 2009; 461: 542-5
40. Wang X, Kim J. Conformation-specific effects of Raf kinase inhibitors . J Med Chem 2012; 55: 7332-41
41. Yadav V, Burke TF, Huber L, Van Horn RD, Zhang Y, Buchanan SG, et al. The CDK4/6 inhibitor LY2835219 overcomes vemurafenib resistance resulting from MAPK reactivation and cyclin D1 upregulation . Mol Cancer Ther 2014; 13: 2253-63
42. Holderfield M, Deuker MM, McCormick F, McMahon M. Targeting RAF kinases for cancer therapy: BRAF-mutated melanoma and beyond. Nat Rev Cancer 2014; 14: 455-67
43. U.S. Cancer Statistics Working Group. United States Cancer Statistics: 1999–2012 Incidence and Mortality Web-based Report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; c2015. Available from: www.cdc.gov/uscs
44. Forbes SA, Bindal N, Bamford S, Cole C, Kok CY, Beare D, et al. COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer. Nucleic Acids Res 2011; 39: D945-50
45. Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan BW, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med 2004; 350: 2129-39
46. Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science 2004; 304: 1497-500
47. Bose R, Kavuri SM, Searleman AC, Shen W, Shen D, Koboldt DC, et al. Activating HER2 mutations in HER2 gene amplification negative breast cancer. Cancer Discov 2013; 3: 224-37
48. Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong XQ, et al. Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem 2012; 287: 28087-98