AurkA inhibitors enhance the effects of B-RAF and MEK inhibitors in melanoma treatment

详细信息    查看全文

• 作者：Emilia Caputo (1)
  Roberta Miceli (2)
  Maria Letizia Motti (3)
  Rosarita Tat茅 (1)
  Federica Fratangelo (2)
  Gerardo Botti (2)
  Nicola Mozzillo (2)
  Maria Vincenza Carriero (2)
  Ernesta Cavalcanti (2)
  Giuseppe Palmieri (4)
  Gennaro Ciliberto (2)
  Giuseppe Pirozzi (2)
  Paolo Antonio Ascierto (2)
  
  1. Institute of Genetics and Biophysics 鈥揑.G.B. ; A. Buzzati-Traverso鈥? CNR ; Via Pietro Castellino ; 111 ; I-80131 ; Naples ; Italy
  2. Istituto Nazionale Tumori Fondazione G. Pascale ; Via M. Semmola ; I-80131 ; Naples ; Italy
  3. Dipartimento di Scienze Motorie e del Benessere ; Universit脿 degli Studi di Napoli 鈥楶arthenope鈥? Via Ammiraglio Ferdinando Acton ; 38 ; I-80133 ; Naples ; Italy
  4. Unit of Cancer Genetics ; Institute of Biomolecular Chemistry (ICB-CNR) ; Traversa La Crucca ; 3 - Baldinca Li Punti ; I-07100 ; Sassari ; Italy
  
• 关键词：Melanoma ; Aurora A kinase ; Targeted therapy ; Combined therapy ; 3D ; human skin reconstruction model
• 刊名：Journal of Translational Medicine
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：12
• 期：1
• 全文大小：1,969 KB
• 参考文献：1. Lens, MB, Dawes, M (2004) Global perspectives of contemporary epidemiological trends of cutaneous malignant melanoma. Br J Dermatol 150: pp. 179-185 CrossRef
  2. Jemal, A, Siegel, R, Ward, E, Hao, Y, Xu, J, Thun, MJ (2009) Cancer statistics. CA Cancer J Clin 59: pp. 225-249 CrossRef
  3. Inumaru, JS, Gordo, KI, Fraga Junior, AC, Silva, AM, Leal, CB, Ayres, FM, Wastowski, IJ, Borges, NF, Saddi, VA (2014) Analysis of the BRAF V600E mutation in primary cutaneous melanoma. Genet Mol Res 13: pp. 2840-2848 CrossRef
  4. Long, GV, Menzies, AM, Nagrial, AM, Haydu, LE, Hamilton, AL, Mann, GJ, Hughes, TM, Thompson, JF, Scolyer, RA, Kefford, RF (2011) Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J Clin Oncol 29: pp. 1239-1246 CrossRef
  5. Sullivan, RJ, Flaherty, K (2013) MAP kinase signaling and inhibition in melanoma. Oncogene 32: pp. 2373-2379 CrossRef
  6. Gray-Schopfer, V, Wellbrock, C, Marais, R (2007) Melanoma biology and new targeted therapy. Nature 445: pp. 851-857 CrossRef
  7. Colombino, M, Capone, M, Lissia, A, Cossu, A, Rubino, C, Giorgi, V, Massi, D, Fonsatti, E, Staibano, S, Nappi, O, Pagani, E, Casula, M, Manca, A, Sini, M, Franco, R, Botti, G, Carac貌, C, Mozzillo, N, Ascierto, PA, Palmieri, G (2012) BRAF/NRAS mutation frequencies among primary tumors and metastases in patients with melanoma. J Clin Oncol 30: pp. 2522-2529 CrossRef
  8. 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 (2002) Mutations of the BRAF gene in human cancer. Nature 417: pp. 949-954 CrossRef
  9. Curtin, JA, Fridlyand, J, Kageshita, T, Patel, HN, Busam, KJ, Kutzner, H, Cho, KH, Aiba, S, Br枚cker, EB, LeBoit, PE, Pinkel, D, Bastian, BC (2005) Distinct sets of genetic alterations in melanoma. N Engl J Med 353: pp. 2135-2147 CrossRef
  10. R眉schoff, J, Kleinschmidt, M, Middel, P (2012) Translational research and diagnostics of melanoma. Pathologe 33: pp. 291-295 CrossRef
  11. Wilmott, JS, Menzies, AM, Haydu, LE, Capper, D, Preusser, M, Zhang, YE, Thompson, JF, Kefford, RF, Deimling, A, Scolyer, RA, Long, GV (2013) BRAF(V600E) protein expression and outcome from BRAF inhibitor treatment in BRAF(V600E) metastatic melanoma. Br J Cancer 108: pp. 924-931 CrossRef
  12. 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鈥搈utant advanced melanoma treated with vemurafenib. N Engl J Med 366: pp. 707-714 CrossRef
  13. 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 (2011) Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J Med 364: pp. 2507-2516 CrossRef
  14. McArthur, GA, Chapman, PB, Robert, C, Larkin, J, Haanen, JB, Dummer, R, Ribas, A, Hogg, D, Hamid, O, Ascierto, PA, Garbe, C, Testori, A, Maio, M, Lorigan, P, Lebb茅, C, Jouary, T, Schadendorf, D, O'Day, SJ, Kirkwood, JM, Eggermont, AM, Dr茅no, B, Sosman, JA, Flaherty, KT, Yin, M, Caro, I, Cheng, S, Trunzer, K, Hauschild, A (2014) Safety and efficacy of vemurafenib in BRAF(V600E) and BRAF(V600K) mutation-positive melanoma (BRIM-3): extended follow-up of a phase 3, randomised, open-label study. Lancet Oncol 15: pp. 323-332 CrossRef
  15. Hauschild, A, Grob, JJ, Demidov, LV, Jouary, T, Gutzmer, R, Millward, M, Rutkowski, P, Blank, CU, Miller, WH, Kaempgen, E, Mart铆n-Algarra, S, Karaszewska, B, Mauch, C, Chiarion-Sileni, V, Martin, AM, Swann, S, Haney, P, Mirakhur, B, Guckert, ME, Goodman, V, Chapman, PB (2012) Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet 380: pp. 358-365 CrossRef
  16. Ascierto, PA, Minor, D, Ribas, A, Lebbe, C, O'Hagan, A, Arya, N, Guckert, M, Schadendorf, D, Kefford, RF, Grob, JJ, Hamid, O, Amaravadi, R, Simeone, E, Wilhelm, T, Kim, KB, Long, GV, Martin, AM, Mazumdar, J, Goodman, VL, Trefzer, U (2013) Phase II trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J Clin Oncol 31: pp. 3205-3211 CrossRef
  17. Jang, S, Atkins, MB (2014) Treatment of BRAF-mutant melanoma: the role of vemurafenib and other therapies. Clin Pharmacol Ther 95: pp. 24-31 CrossRef
  18. Liu, D, Liu, X, Xing, M (2014) Activities of multiple cancer-related pathways are associated with BRAF mutation and predict the resistance to BRAF/MEK inhibitors in melanoma cells. Cell Cycle 13: pp. 208-219 CrossRef
  19. Trunzer, K, Pavlick, AC, Schuchter, L, Gonzalez, R, McArthur, GA, Hutson, TE, Moschos, SJ, Flaherty, KT, Kim, KB, Weber, JS, Hersey, P, Long, GV, Lawrence, D, Ott, PA, Amaravadi, RK, Lewis, KD, Puzanov, I, Lo, RS, Koehler, A, Kockx, M, Spleiss, O, Schell-Steven, A, Gilbert, HN, Cockey, L, Bollag, G, Lee, RJ, Joe, AK, Sosman, JA, Ribas, A (2013) Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J Clin Oncol 31: pp. 1767-1774 CrossRef
  20. Shi, H, Hugo, W, Kong, X, Hong, A, Koya, RC, Moriceau, G, Chodon, T, Guo, R, Johnson, DB, Dahlman, KB, Kelley, MC, Kefford, RF, Chmielowski, B, Glaspy, JA, Sosman, JA, Baren, N, Long, GV, Ribas, A, Lo, RS (2014) Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov 4: pp. 80-93 CrossRef
  21. 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 (2014) The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov 4: pp. 94-109 CrossRef
  22. Olsazanski, AJ (2014) Current and future roles of targeted therapy and immunotherapy in advanced melanoma. J Manag Care Pharm 20: pp. 346-356
  23. Wang, X, Moschos, SJ, Becker, D (2010) Functional analysis and molecular targeting of aurora kinases A and B in advanced melanoma. Genes Cancer 1: pp. 952-963 CrossRef
  24. Tsai, J, Lee, JT, Wang, W, Zhang, J, Cho, H, Mamo, S, Bremer, R, Gillette, S, Kong, J, Haass, NK, Sproesser, K, Li, L, Smalley, KS, Fong, D, Zhu, YL, Marimuthu, A, Nguyen, H, Lam, B, Liu, J, Cheung, I, Rice, J, Suzuki, Y, Luu, C, Settachatgul, C, Shellooe, R, Cantwell, J, Kim, SH, Schlessinger, J, Zhang, KY, West, BL (2008) Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity. Proc Natl Acad Sci 105: pp. 3041-3046 CrossRef
  25. Grimaldi, AM, Simeone, E, Ascierto, PA (2014) The role of MEK inhibitors in the treatment of metastatic melanoma. Curr Opin Oncol 26: pp. 196-203 CrossRef
  26. Flaherty, KT, Infante, JR, Daud, A, Gonzalez, R, Kefford, RF, Sosman, J, Hamid, O, Schuchter, L, Cebon, J, Ibrahim, N, Kudchadkar, R, Burris, HA, 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 (2012) Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 367: pp. 1694-1703 CrossRef
  27. Sheppard, KE, Cullinane, C, Hannan, KM, Wall, M, Chan, J, Barber, F, Foo, J, Cameron, D, Neilsen, A, Ng, P, Ellul, J, Kleinschmidt, M, Kinross, KM, Bowtell, DD, Christensen, JG, Hicks, RJ, Johnstone, RW, McArthur, GA, Hannan, RD, Phillips, WA, Pearson, RB (2013) Synergistic inhibition of ovarian cancer cell growth by combining selective PI3K/mTOR and RAS/ERK pathway inhibitors. Eur J Cancer 49: pp. 3936-3944 CrossRef
  28. Kim, KB, Kefford, R, Pavlick, AC, Infante, JR, Ribas, A, Sosman, JA, Fecher, LA, Millward, M, McArthur, GA, Hwu, P, Gonzalez, R, Ott, PA, Long, GV, Gardner, OS, Ouellet, D, Xu, Y, DeMarini, DJ, Le, NT, Patel, K, Lewis, KD (2013) Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol 31: pp. 482-489 CrossRef
  29. Vader, G, Lens, SM (2008) The Aurora kinase family in cell division and cancer. Biochim Biophys Acta 1786: pp. 60-72
  30. Nikonova, AS, Astsaturov, I, Serebriiskii, IG, Dunbrack, RL, Golemis, EA (2013) Aurora A kinase (AURKA) in normal and pathological cell division. Cell Mol Life Sci 70: pp. 661-687 CrossRef
  31. Reiter, R, Gais, P, J眉tting, U, Steuer-Vogt, MK, Pickhard, A, Bink, K, Rauser, S, Lassmann, S, H枚fler, H, Werner, M, Walch, A (2006) Aurora kinase A messenger RNA overexpression is correlated with tumor progression and shortened survival in head and neck squamous cell carcinoma. Clin Cancer Res 12: pp. 5136-5141 CrossRef
  32. Nishida, N, Nagasaka, T, Kashiwagi, K, Boland, CR, Goel, A (2007) High copy amplification of the Aurora-A gene is associated with chromosomal instability phenotype in human colorectal cancers. Cancer Biol Ther 6: pp. 525-533 CrossRef
  33. Nadler, Y, Camp, RL, Schwartz, C, Rimm, DL, Kluger, HM, Kluger, Y (2008) Expression of Aurora A (but not Aurora B) is predictive of survival in breast cancer. Clin Cancer Res 14: pp. 4455-4462 CrossRef
  34. Liu, Y, Hawkins, OE, Su, Y, Vilgelm, AE, Sobolik, T, Thu, YM, Kantrow, S, Splittgerber, RC, Short, S, Amiri, KI, Ecsedy, JA, Sosman, JA, Kelley, MC, Richmond, A (2013) Targeting aurora kinases limits tumour growth through DNA damage-mediated senescence and blockade of NF-魏B impairs this drug-induced senescence. EMBO Mol Med 5: pp. 149-166 mmm.201201378" target="_blank" title="It opens in new window">CrossRef
  35. Limame, R, Wouters, A, Pauwels, B, Fransen, E, Peeters, M, Lardon, F, Wever, O, Pauwels, P (2012) Comparative analysis of dynamic cell viability, migration and invasion assessments by novel real-time technology and classic endpoint assays. PLoS One 7: pp. e46536 CrossRef
  36. Chang, F, Steelman, LS, Lee, JT, Shelton, JG, Navolanic, PM, Blalock, WL, Franklin, RA, McCubrey, JA (2003) Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokine receptors to transcription factors: potential targeting for therapeutic intervention. Leukemia 17: pp. 1263-1293 CrossRef
  37. Katayama, H, Sasai, K, Kawai, H, Yuan, ZM, Bondaruk, J, Suzuki, F, Fujii, S, Arlinghaus, RB, Czerniak, BA, Sen, S (2004) Phosphorylation by aurora kinase A induces Mdm2-mediated destabilization and inhibition of p53. Nat Genet 36: pp. 55-62 CrossRef
  38. Pirozzi, G, Tirino, V, Camerlingo, R, Franco, R, Rocca, A, Liguori, E, Martucci, N, Paino, F, Normanno, N, Rocco, G (2011) Epithelial to mesenchymal transition by TGF尾-1 induction increases stemness characteristics in primary non small cell lung cancer cell line. PLoS One 6: pp. e21548 CrossRef
  39. Tirino, V, Camerlingo, R, Bifulco, K, Irollo, E, Montella, R, Paino, F, Sessa, G, Carriero, MV, Normanno, N, Rocco, G, Pirozzi, G (2013) TGF-尾1 exposure induces epithelial to mesenchymal transition both in CSCs and non-CSCs of the A549 cell line, leading to an increase of migration ability in the CD133+ A549 cell fraction. Cell Death Dis 4: pp. e620 CrossRef
  
• 刊物主题：Biomedicine general; Medicine/Public Health, general;
• 出版者：BioMed Central
• ISSN：1479-5876

文摘

Background Aurora kinase A (AurkA) is over-expressed in melanoma and its inhibition has been observed to limit tumor growth, suggesting a potential role in melanoma treatment. Methods A human melanoma cell line with the B-RAF (V600E) mutation (A375mel) was exposed to B-RAF inhibitor (GSK2118436), MEK inhibitor (GSK1120212) and AurkA inhibitor (MLN8054) as single agents or in various combinations (BRAF plus AurkA inhibitor, MEK plus AurkA inhibitor or triple combination BRAF plus MEK plus AurkA inhibitor). Cell proliferation was assessed using xCELLigence technology. Total protein extracts were examined for p53 and c-Myc protein expression by Western blot analysis. Drug anti-tumor effects were further assessed using a 3D-human melanoma skin reconstruction model, in which tissues were incubated with serum-free medium containing control, B-RAF plus MEK inhibitor, MEK plus AurkA inhibitor or the triple combination. Results AurkA inhibitor plus B-RAF inhibitor, AurkA inhibitor plus MEK inhibitor or triple combination had a markedly greater anti-proliferative effect on A375 (BRAFV600E) melanoma cells than single agents. In the 3D human skin model, the triple combination had a greater anti-tumor effect at the epidermal/dermal junction than control or either double combination. However, S-100 and Ki-67 positively stained spindle-shaped cells were detected in the dermal stratum, suggesting the presence of alive and proliferating melanoma cells. Conclusions These findings provide new prospects for melanoma research, including combined B-RAF/AurkA inhibition for B-RAF mutated melanomas and MEK/AurkA inhibitor combination for patients without B-RAF mutations. Moreover, for the first time, we have shown that a B-RAF, MEK and AurkA inhibitor triple drug combination offers increased efficacy against melanoma cell growth and might be considered as a potential treatment strategy for enhancing clinical response in melanoma. However, although this triple drug combination was more effective at the epidermal/dermal junction, the suggested presence of alive and proliferating melanoma cells in the dermal stratum could result in drug resistance and disease recurrence. Molecular characterization of these dermal cells may be critical for the development of novel therapeutic strategies.