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Journal of Skin Cancer
Volume 2011 (2011), Article ID 423239, 8 pages
http://dx.doi.org/10.1155/2011/423239
Review Article

BRAF in Melanoma: Pathogenesis, Diagnosis, Inhibition, and Resistance

1Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02114, USA
2Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA

Received 10 July 2011; Revised 27 September 2011; Accepted 28 September 2011

Academic Editor: S. Ugurel

Copyright © 2011 Ryan J. Sullivan and Keith T. Flaherty. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Linked References

  1. A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA Cancer Journal for Clinicians, vol. 60, no. 5, pp. 277–300, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  2. http://seer.cancer.gov/.
  3. H. Davies, G. R. Bignell, C. Cox et al., “Mutations of the BRAF gene in human cancer,” Nature, vol. 417, no. 6892, pp. 949–954, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  4. P. M. Pollock, U. L. Harper, K. S. Hansen et al., “High frequency of BRAF mutations in nevi,” Nature Genetics, vol. 33, no. 1, pp. 19–20, 2003. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  5. A. Sharma, N. R. Trivedi, M. A. Zimmerman, D. A. Tuveson, C. D. Smith, and G. P. Robertson, “Mutant V599EB-Raf regulates growth and vascular development of malignant melanoma tumors,” Cancer Research, vol. 65, no. 6, pp. 2412–2421, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  6. L. A. Fecher, R. K. Amaravadi, and K. T. Flaherty, “The MAPK pathway in melanoma,” Current Opinion in Oncology, vol. 20, no. 2, pp. 183–189, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  7. J. Tsai, J. T. Lee, W. Wang et al., “Discovery of a selective inhibitor of oncogenic B-Raf kinase with potent antimelanoma activity,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 8, pp. 3041–3046, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  8. J. L. Bos, “ras Oncogenes in human cancer: a review,” Cancer Research, vol. 49, no. 17, pp. 4682–4689, 1989. View at Scopus
  9. A. P. Albino, R. Le Strange, A. I. Oliff, M. E. Furth, and L. J. Old, “Transforming ras genes from human melanoma: a manifestation of tumour heterogeneity?” Nature, vol. 308, no. 5954, pp. 69–72, 1984. View at Scopus
  10. N. J. Ball, J. J. Yohn, J. G. Morelli, D. A. Norris, L. E. Golitz, and J. P. Hoeffler, “RAS mutations in human melanoma: a marker of malignant progression,” Journal of Investigative Dermatology, vol. 102, no. 3, pp. 285–290, 1994. View at Scopus
  11. A. Platz, U. Ringborg, E. Mansson Brahme, and B. Lagerlof, “Melanoma metastases from patients with hereditary cutaneous malignant melanoma contain a high frequency of N-ras activating mutations,” Melanoma Research, vol. 4, no. 3, pp. 169–177, 1994. View at Publisher · View at Google Scholar · View at Scopus
  12. L. J. Van 't Veer, B. M. T. Burgering, R. Versteeg et al., “N-ras mutations in human cutaneous melanoma from sun-exposed body sites,” Molecular and Cellular Biology, vol. 9, no. 7, pp. 3114–3116, 1989. View at Scopus
  13. A. A. Adjei, “Blocking oncogenic Ras signaling for cancer therapy,” Journal of the National Cancer Institute, vol. 93, no. 14, pp. 1062–1074, 2001. View at Scopus
  14. M. Beeram, A. Patnaik, and E. K. Rowinsky, “Raf: a strategic target for therapeutic development against cancer,” Journal of Clinical Oncology, vol. 23, no. 27, pp. 6771–6790, 2005. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  15. N. Dumaz, R. Hayward, J. Martin et al., “In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling,” Cancer Research, vol. 66, no. 19, pp. 9483–9491, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  16. A. Jarry, D. Masson, E. Cassagnau, S. Parois, C. Laboisse, and M. G. Denis, “Real-time allele-specific amplification for sensitive detection of the BRAF mutation V600E,” Molecular and Cellular Probes, vol. 18, no. 5, pp. 349–352, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  17. C. J. Miller, M. Cheung, A. Sharma et al., “Method of mutation analysis may contribute to discrepancies in reports of V599EBRAF mutation frequencies in melanocytic neoplasms [1],” Journal of Investigative Dermatology, vol. 123, no. 5, pp. 990–992, 2004. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  18. J. Lin, Y. Goto, H. Murata et al., “Polyclonality of BRAF mutations in primary melanoma and the selection of mutant alleles during progression,” British Journal of Cancer, vol. 104, no. 3, pp. 464–468, 2011. View at Publisher · View at Google Scholar · View at PubMed
  19. J. Dong, R. G. Phelps, R. Qiao et al., “BRAF oncogenic mutations correlate with progression rather than initiation of human melanoma,” Cancer Research, vol. 63, no. 14, pp. 3883–3885, 2003. View at Scopus
  20. K. Omholt, A. Platz, L. Kanter, U. Ringborg, and J. Hansson, “NRAS and BRAF mutations arise early during melanoma pathogenesis and are preserved throughout tumor progression,” Clinical Cancer Research, vol. 9, no. 17, pp. 6483–6488, 2003. View at Scopus
  21. G. Ellison, E. Donald, G. McWalter et al., “A comparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples,” Journal of Experimental and Clinical Cancer Research, vol. 29, no. 1, article 132, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  22. R. P. Oldenburg, M. S. Liu, and M. S. Kolodney, “Selective amplification of rare mutations using locked nucleic acid oligonucleotides that competitively inhibit primer binding to wild-type DNA,” Journal of Investigative Dermatology, vol. 128, no. 2, pp. 398–402, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  23. D. J. Panka, R. J. Sullivan, and J. W. Mier, “An inexpensive, specific and highly sensitive protocol to detect the BrafV600E mutation in melanoma tumor biopsies and blood,” Melanoma Research, vol. 20, no. 5, pp. 401–407, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  24. P. Pinzani, C. Santucci, I. Mancini et al., “BRAFV600E detection in melanoma is highly improved by COLD-PCR,” Clinica Chimica Acta, vol. 412, no. 11-12, pp. 901–905, 2011. View at Publisher · View at Google Scholar · View at PubMed
  25. M. Yancovitz, J. Yoon, M. Mikhail et al., “Detection of mutant BRAF alleles in the plasma of patients with metastatic melanoma,” Journal of Molecular Diagnostics, vol. 9, no. 2, pp. 178–183, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  26. R. E. Board, G. Ellison, M. C. M. Orr et al., “Detection of BRAF mutations in the tumour and serum of patients enrolled in the AZD6244 (ARRY-142886) advanced melanoma phase II study,” British Journal of Cancer, vol. 101, no. 10, pp. 1724–1730, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  27. M. Shinozaki, S. J. O'Day, M. Kitago et al., “Utility of circulating B-RAF DNA mutation in serum for monitoring melanoma patients receiving biochemotherapy,” Clinical Cancer Research, vol. 13, no. 7, pp. 2068–2074, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  28. M. Daniotti, V. Vallacchi, L. Rivoltini et al., “Detection of mutated BRAFV600E variant in circulating DNA of stage III-IV melanoma patients,” International Journal of Cancer, vol. 120, no. 11, pp. 2439–2444, 2007. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  29. P. Pinzani, F. Salvianti, R. Cascella et al., “Allele specific Taqman-based real-time PCR assay to quantify circulating BRAFV600E mutated DNA in plasma of melanoma patients,” Clinica Chimica Acta, vol. 411, no. 17-18, pp. 1319–1324, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  30. M. Kitago, K. Koyanagi, T. Nakamura et al., “MRNA expression and BRAF mutation in circulating melanoma cells isolated from peripheral blood with High molecular weight melanoma-associated antigen-specific monoclonal antibody beads,” Clinical Chemistry, vol. 55, no. 4, pp. 757–764, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  31. S. Gabriel and L. Ziaugra, “SNP genotyping using Sequenom MassARRAY 7K platform,” Current Protocols in Human Genetics, chapter 2, unit 2.12, 2004. View at Scopus
  32. S. Gabriel, L. Ziaugra, and D. Tabbaa, “SNP genotyping using the sequenom massARRAY iPLEX Platform,” Current Protocols in Human Genetics, chapter 2, unit 2.12, no. 60, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  33. S. R. Moore, D. L. Persons, J. A. Sosman et al., “Detection of copy number alterations in metastatic melanoma by a DNA fluorescence in situ hybridization probe panel and array comparative genomic hybridization: a southwest oncology group study (S9431),” Clinical Cancer Research, vol. 14, no. 10, pp. 2927–2935, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  34. M. S. Boguski, R. Arnaout, and C. Hill, “Customized care 2020: how medical sequencing and network biology will enable personalized medicine,” F1000 Biology Reports, vol. 1, 2009.
  35. S. J. M. Jones, J. Laskin, Y. Y. Li et al., “Evolution of an adenocarcinoma in response to selection by targeted kinase inhibitors,” Genome Biology, vol. 11, article R82, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  36. T. Eisen, T. Ahmad, K. T. Flaherty et al., “Sorafenib in advanced melanoma: a Phase II randomised discontinuation trial analysis,” British Journal of Cancer, vol. 95, no. 5, pp. 581–586, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  37. R. K. Amaravadi, L. M. Schuchter, D. F. McDermott et al., “Phase II trial of temozolomide and sorafenib in advanced melanoma patients with or without brain metastases,” Clinical Cancer Research, vol. 15, no. 24, pp. 7711–7718, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  38. D. F. McDermott, J. A. Sosman, R. Gonzalez et al., “Double-blind randomized phase II study of the combination of sorafenib and dacarbazine in patients with advanced melanoma: a report from the 11715 study group,” Journal of Clinical Oncology, vol. 26, no. 13, pp. 2178–2185, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  39. K. T. Flaherty, J. Schiller, L. M. Schuchter et al., “A Phase I trial of the oral, multikinase inhibitor sorafenib in combination with carboplatin and paclitaxel,” Clinical Cancer Research, vol. 14, no. 15, pp. 4836–4842, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  40. A. Hauschild, S. S. Agarwala, U. Trefzer et al., “Results of a phase III, randomized, placebo-controlled study of sorafenib in combination with carboplatin and paclitaxel as second-line treatment in patients with unresectable stage III or stage IV melanoma,” Journal of Clinical Oncology, vol. 27, no. 17, pp. 2823–2830, 2009. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  41. K. T. Flaherty, S. J. Lee, L. M. Schuchter, et al., “Final results of E2603: a double-blind, randomized phase III trial comparing carboplatin/paclitaxel (P) with or without sorafenib (S) in metastatic melanoma,” Journal of Clinical Oncology, vol. 28, p. 8511, 2010.
  42. K. T. Flaherty, I. Puzanov, K. B. Kim et al., “Inhibition of mutated, activated BRAF in metastatic melanoma,” New England Journal of Medicine, vol. 363, no. 9, pp. 809–819, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  43. G. Bollag, P. Hirth, J. Tsai et al., “Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma,” Nature, vol. 467, no. 7315, pp. 596–599, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  44. E. W. Joseph, C. A. Pratilas, P. I. Poulikakos et al., “The RAF inhibitor PLX4032 inhibits ERK signaling and tumor cell proliferation in a V600E BRAF-selective manner,” Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 33, pp. 14903–14908, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  45. C. C. Jiang, F. Lai, K. H. Tay et al., “Apoptosis of human melanoma cells induced by inhibition of B-RAF V600E involves preferential splicing of bimS,” Cell Death and Disease, vol. 1, no. 9, article e69, 2010. View at Publisher · View at Google Scholar · View at PubMed
  46. A. Ribas, K. B. Kim, L. M. Schucter, et al., “BRIM-2: an open-label, multicenter phase II study of vemurafenib in previously treated patients with BRAF V600E mutation-positive metastatic melanoma,” Journal of Clinical Oncology, vol. 29, 2011.
  47. P. B. Chapman, A. Hauschild, C. Robert et al., “Improved survival with vemurafenib in melanoma with BRAF V600E mutation,” New England Journal of Medicine, vol. 364, no. 26, pp. 2507–2516, 2011. View at Publisher · View at Google Scholar · View at PubMed
  48. R. Kefford, H. Arkenau, M. P. Brown, et al., “Phase I/II study of GSK2118436, a selective inhibitor of oncogenic mutant BRAF kinase, in patients with metastatic melanoma and other solid tumors,” Journal of Clinical Oncology, vol. 28, abstract 8503, 2010.
  49. D. B. Solit, L. A. Garraway, C. A. Pratilas et al., “BRAF mutation predicts sensitivity to MEK inhibition,” Nature, vol. 439, no. 7074, pp. 358–362, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  50. A. A. Adjei, R. B. Cohen, W. Franklin et al., “Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers,” Journal of Clinical Oncology, vol. 26, no. 13, pp. 2139–2146, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  51. U. Banerji, D. R. Camidge, H. M. W. Verheul et al., “The first-in-human study of the hydrogen sulfate (hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer,” Clinical Cancer Research, vol. 16, no. 5, pp. 1613–1623, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  52. N. K. Haass, K. Sproesser, T. K. Nguyen et al., “The mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor AZD6244 (ARRY-142886) induces growth arrest in melanoma cells and tumor regression when combined with docetaxel,” Clinical Cancer Research, vol. 14, no. 1, pp. 230–239, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  53. S. P. Patel, A. J. Lazar, S. Mahoney, et al., “Clinical responses to AZD6244 (ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma,” Journal of Clinical Oncology, vol. 28, abstract 8501, 2010.
  54. J. R. Infante, L. A. Fecher, S. Nallapareddy, et al., “Safety and efficacy results from the first-in-human study of the oral MEK 1/2 inhibitor GSK1120212,” Journal of Clinical Oncology, vol. 28, abstract 2503, 2010.
  55. P. M. LoRusso, S. S. Krishnamurthi, J. J. Rinehart et al., “Phase I pharmacokinetic and pharmacodynamic study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced cancers,” Clinical Cancer Research, vol. 16, no. 6, pp. 1924–1937, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  56. J. Delord, N. Houede, A. Awada, et al., “First-in-human phase I safety, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the oral MEK-inhibitor AS703026 (two regimens [R]) in patients (pts) with advanced solid tumors,” Journal of Clinical Oncology, vol. 28, absrtact 2504, 2010.
  57. C. Roche-Lestienne, V. Soenen-Cornu, N. Grardel-Duflos et al., “Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571, and they can pre-exist to the onset of treatment,” Blood, vol. 100, no. 3, pp. 1014–1018, 2002. View at Publisher · View at Google Scholar · View at Scopus
  58. S. Roumiantsev, N. P. Shah, M. E. Gorre et al., “Clinical resistance to the kinase inhibitor STI-571 in chronic myeloid leukemia by mutation of Tyr-253 in the Abl kinase domain P-loop,” Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 16, pp. 10700–10705, 2002. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  59. E. Wardelmann, S. Merkelbach-Bruse, K. Pauls et al., “Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate,” Clinical Cancer Research, vol. 12, no. 6, pp. 1743–1749, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  60. W. D. Tap, K. W. Gong, J. Dering et al., “Pharmacodynamic characterization of the efficacy signals due to selective BRAF inhibition with PLX4032 in malignant melanoma,” Neoplasia, vol. 12, no. 8, pp. 637–649, 2010. View at Publisher · View at Google Scholar · View at Scopus
  61. C. M. Johannessen, J. S. Boehm, S. Y. Kim et al., “COT drives resistance to RAF inhibition through MAP kinase pathway reactivation,” Nature, vol. 468, no. 7326, pp. 968–972, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  62. R. Nazarian, H. Shi, Q. Wang et al., “Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation,” Nature, vol. 468, no. 7326, pp. 973–977, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  63. C. Montagut, S. V. Sharma, T. Shioda et al., “Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma,” Cancer Research, vol. 68, no. 12, pp. 4853–4861, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  64. N. Wagle, C. Emery, M. F. Berger, et al., “Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling,” Journal of Clinical Oncology, vol. 29, pp. 3085–3096, 2011.
  65. H. Wang, S. Daouti, W. -H. Li et al., “Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-Raf V600E mutation,” Cancer Research, vol. 71, no. 16, pp. 5535–5545, 2011. View at Publisher · View at Google Scholar · View at PubMed
  66. J. Villanueva, A. Vultur, J. T. Lee et al., “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, vol. 18, no. 6, pp. 683–695, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  67. K. S. M. Smalley, M. Lioni, M. D. Palma et al., “Increased cyclin D1 expression can mediate BRAF inhibitor resistance in BRAF V600E-mutated melanomas,” Molecular Cancer Therapeutics, vol. 7, no. 9, pp. 2876–2883, 2008. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  68. R. Halaban, W. Zhang, A. Bacchiocchi et al., “PLX4032, a selective BRAFV600E kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAFWT melanoma cells,” Pigment Cell and Melanoma Research, vol. 23, no. 2, pp. 190–200, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  69. G. Hatzivassiliou, K. Song, I. Yen et al., “RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth,” Nature, vol. 464, no. 7287, pp. 431–435, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  70. S. J. Heidorn, C. Milagre, S. Whittaker et al., “Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF,” Cell, vol. 140, no. 2, pp. 209–221, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  71. P. I. Poulikakos, C. Zhang, G. Bollag, K. M. Shokat, and N. Rosen, “RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF,” Nature, vol. 464, no. 7287, pp. 427–430, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  72. F. M. Kaplan, Y. Shao, M. M. Mayberry, and A. E. Aplin, “Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells,” Oncogene, vol. 30, pp. 366–371, 2011. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  73. J. R. Infante, G. S. Falchook, D. P. Lawrence, et al., “Phase I/II study to assess safety, pharmacokinetics, and efficacy of the oral MEK 1/2 inhibitor GSK1120212 (GSK212) dosed in combination with the oral BRAF inhibitor GSK2118436 (GSK436),” Journal of Clinical Oncology, vol. 29, 2011.
  74. M. Verhaegen, J. A. Bauer, C. M. De La Vega et al., “A novel BH3 mimetic reveals a mitogen-activated protein kinase-dependent mechanism of melanoma cell death controlled by p53 and reactive oxygen species,” Cancer Research, vol. 66, no. 23, pp. 11348–11359, 2006. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  75. F. S. Hodi, S. J. O'Day, D. F. McDermott et al., “Improved survival with ipilimumab in patients with metastatic melanoma,” New England Journal of Medicine, vol. 363, no. 8, pp. 711–723, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  76. M. Sznol, J. D. Powderly, D. C. Smith, et al., “Safety and antitumor activity of biweekly MDX-1106 (Anti-PD-1, BMS-936558/ONO-4538) in patients with advanced refractory malignancies,” Journal of Clinical Oncology, vol. 28, abstract 2506, 2010.
  77. B. Comin-Anduix, T. Chodon, H. Sazegar et al., “The oncogenic BRAF kinase inhibitor PLX4032/RG7204 does not affect the viability or function of human lymphocytes across a wide range of concentrations,” Clinical Cancer Research, vol. 16, no. 24, pp. 6040–6048, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus
  78. A. Boni, A. P. Cogdill, P. Dang et al., “Selective BRAFV600E inhibition enhances T-cell recognition of melanoma without affecting lymphocyte function,” Cancer Research, vol. 70, no. 13, pp. 5213–5219, 2010. View at Publisher · View at Google Scholar · View at PubMed · View at Scopus