Targeting oncogenic BRAF and aberrant MAPK activation in the treatment of cutaneous melanoma

Critical Reviews in Oncology/Hematology

Volumn 96, Issue 3, 2015, Pages 385-398

  Carlino, Matteo S ^a,b,c,d   Long, Georgina V ^c,d,e   Kefford, Richard F ^a,b,c,f   Rizos, Helen ^b,c,f  

^a WESTMEAD HOSPITAL   (Australia)

^b WESTMEAD HOSPITAL   (Australia)

^c MELANOMA INSTITUTE AUSTRALIA   (Australia)

^d UNIVERSITY OF SYDNEY   (Australia)

^e Mater Hospital   (Australia)

^f MACQUARIE UNIVERSITY   (Australia)

Author keywords

BRAF inhibitors; BRAF mutations; MEK inhibitors; Melanoma; Resistance; Targeted therapy

Indexed keywords

B RAF KINASE; B RAF KINASE INHIBITOR; BINIMETINIB; COBIMETINIB; DABRAFENIB; DACARBAZINE; ENCORAFENIB; GEFITINIB; IPILIMUMAB; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; MITOGEN ACTIVATED PROTEIN KINASE KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE KINASE 2; NIVOLUMAB; PEMBROLIZUMAB; PHOSPHATIDYLINOSITOL 3 KINASE; PROTEIN KINASE B; PROTEIN TYROSINE KINASE; RAF PROTEIN; SELUMETINIB; TRAMETINIB; VEMURAFENIB; PROTEIN KINASE INHIBITOR;

AKT GENE; BRAF GENE; BRAIN METASTASIS; CANCER CHEMOTHERAPY; CANCER GROWTH; CANCER PROGNOSIS; CELL METABOLISM; COPY NUMBER VARIATION; COT GENE; CRAF GENE; CUTANEOUS MELANOMA; DRUG EFFICACY; DRUG RESPONSE; DRUG SAFETY; DRUG TARGETING; DRUG TREATMENT FAILURE; ENZYME ACTIVATION; ENZYME INHIBITION; FEEDBACK SYSTEM; GENE; GENE FREQUENCY; GENE MUTATION; GENE OVEREXPRESSION; GENOTYPE; HUMAN; MAPK GENE; MEK1 GENE; MEK2 GENE; ONCOGENE K RAS; ONCOGENE N RAS; OPEN READING FRAME; OVERALL SURVIVAL; PHASE 1 CLINICAL TRIAL (TOPIC); PHASE 2 CLINICAL TRIAL (TOPIC); PHASE 3 CLINICAL TRIAL (TOPIC); PHASE 4 CLINICAL TRIAL (TOPIC); PI3K GENE; PROGRESSION FREE SURVIVAL; PROTEIN EXPRESSION; RANDOMIZED CONTROLLED TRIAL (TOPIC); REVIEW; RTK GENE; SIGNAL TRANSDUCTION; TREATMENT WITHDRAWAL; TUMOR INVASION; TUMOR XENOGRAFT; UPREGULATION; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; MELANOMA;

HUMANS; MAP KINASE SIGNALING SYSTEM; MELANOMA; PROTEIN KINASE INHIBITORS; PROTO-ONCOGENE PROTEINS B-RAF;

EID: 84983103421     PISSN: 10408428     EISSN: 18790461     Source Type: Journal    
DOI: 10.1016/j.critrevonc.2015.08.021     Document Type: Review

References (177)

1. Abel E.V., Basile K.J., Kugel C.H., 3rd W., itkiewicz A.K., Le K., Amaravadi R.K., et al. Melanoma adapts to RAF/MEK inhibitors through FOXD3-mediated upregulation of ERBB3. J. Clin. Invest. 2013, 123:2155-2168.
2. Ackerman A., Klein O., McDermott D.F., Wang W., Ibrahim N., Lawrence D.P., et al. Outcomes of patients with metastatic melanoma treated with immunotherapy prior to or after BRAF inhibitors. Cancer 2014, 120:1695-1701.
3. Andrews M.C., Behren A., Chionh F., Mariadason J., Vella L.J., Do H., et al. BRAF inhibitor-driven tumor proliferation in a KRAS-mutated colon carcinoma is not overcome by MEK1/2 inhibition. J. Clin. Oncol. 2013, 31:e448-e451.
4. Anforth R., Fernandez-Penas P., Long G.V. Cutaneous toxicities of RAF inhibitors. Lancet Oncol. 2013, 14:e11-e18.
5. Ascierto P.A., Simeone E., Giannarelli D., Grimaldi A.M., Romano A., Mozzillo N. Sequencing of BRAF inhibitors and ipilimumab in patients with metastatic melanoma: a possible algorithm for clinical use. J. Transl. Med. 2012, 10:107.
6. Ascierto P.A., Schadendorf D., Berking C., Agarwala S.S., van H., erpen C.M., Queirolo P., et al. MEK162 for patients with advanced melanoma harbouring NRAS or Val600 BRAF mutations: a non-randomised, open-label phase 2 study. Lancet Oncol. 2013, 14:249-256.
7. Ascierto P.A., Minor D., Ribas A., Lebbe C., O'Hagan A., Arya N., et al.Phase I.I. trial (BREAK-2) of the BRAF inhibitor dabrafenib (GSK2118436) in patients with metastatic melanoma. J. Clin. Oncol. 2013, 31:3205-3211.
8. Bahadoran P., Allegra M., Le D., uff F., Long-Mira E., Hofman P., Giacchero D., et al. Major clinical response to a BRAF inhibitor in a patient with a BRAF L597R-mutated melanoma. J. Clin. Oncol. 2013, 31:e324-e326.
9. Bollag G., Hirth P., Tsai J., Zhang J., Ibrahim P.N., Cho H., et al. Clinical efficacy of a RAF inhibitor needs broad target blockade in BRAF-mutant melanoma. Nature 2010, 467:596-599.
10. Bowyer S.E., Rao A.D., Lyle M., Sandhu S., Long G.V., McArthur G.A., et al. Activity of trametinib in K601E and L597Q BRAF mutation-positive metastatic melanoma. Melanoma Res. 2014, 24:504-508.
11. Brissy S., Gaudy-Marqueste C., Mallet S., Monestier S., Hesse S., Koeppel M.-C., et al. BRAF mutation as a pejorative marker in metastatic melanoma. ASCO Meet. Abstr. 2012, 30:8555.
12. Brondello J.M., Brunet A., Pouyssegur J., McKenzie F.R. The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade. J. Biol. Chem. 1997, 272:1368-1376.
13. Burotto M., Chiou V.L., Lee J.M., Kohn E.C. The MAPK pathway across different malignancies: a new perspective. Cancer 2014, 120:3446-3456.
14. Busser B., Leccia M.T., Gras-Combe G., Bricault I., Templier I., Claeys A., et al. Identification of a novel complex BRAF mutation associated with major clinical response to vemurafenib in a patient with metastatic melanoma. JAMA Dermatol. 2013, 149:1403-1406.
15. Callahan M.K., Rampal R., Harding J.J., Klimek V.M., Chung Y.R., Merghoub T., et al. Progression of RAS-mutant leukemia during RAF inhibitor treatment. N. Engl. J. Med. 2012, 367:2316-2321.
16. Carlino M.S., Gowrishankar K., Saunders C.A.B., Pupo G.M., Snoyman S., Zhang X.D., et al. Antiproliferative effects of continued mitogen-activated protein kinase pathway inhibition following acquired resistance to BRAF and/or MEK inhibition in melanoma. Mol. Cancer Ther. 2013, 12:1332-1342.
17. Carlino M.S., Todd J.R., Rizos H. Resistance to c-Kit inhibitors in melanoma: insights for future therapies. Oncoscience 2014, 1:423-426.
18. Carlino M.S., Todd J.R., Gowrishankar K., Mijatov B., Pupo G.M., Fung C., et al. Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma. Mol. Oncol. 2014, 8:544-554.
19. Carlino M.S., Haydu L.E., Kakavand H., Menzies A.M., Hamilton A.L., Yu B., et al. Correlation of BRAF and NRAS mutation status with outcome, site of distant metastasis and response to chemotherapy in metastatic melanoma. Br. J. Cancer 2014, 111:292-299.
20. Carlino M.S., Kwan V., Miller D.K., Saunders C.A., Yip D., Nagrial A.M., et al. New RAS-mutant pancreatic adenocarcinoma with combined BRAF and MEK inhibition for metastatic melanoma. J. Clin. Oncol. 2015, 33:e52-e56.
21. Carlino M.S., Fung C., Shahheydari H., Todd J.R., Boyd S.C., Irvine M., et al. Preexisting MEK1P124 mutations diminish response to BRAF inhibitors in metastatic melanoma patients. Clin. Cancer Res. 2015, 21:98-105.
22. Carvajal R.D., Antonescu C.R., Wolchok J.D., Chapman P.B., Roman R.A., Teitcher J., et al. KIT as a therapeutic target in metastatic melanoma. JAMA 2011, 305:2327-2334.
23. Castellano E., Downward J. RAS interaction with PI3K: more than just another effector pathway. Genes Cancer 2011, 2:261-274.
24. Chan M.M., Haydu L.E., Menzies A.M., Azer M.W., Klein O., Lyle M., et al. The nature and management of metastatic melanoma after progression on BRAF inhibitors: effects of extended BRAF inhibition. Cancer 2014, 120:3142-3153.
25. Chapman P.B., Hauschild A., Robert C., Haanen J.B., Ascierto P., Larkin J., et al. Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N. Engl. J. Med. 2011, 364:2507-2516.
26. Cohen C., Zavala-Pompa A., Sequeira J.H., Shoji M., Sexton D.G., Cotsonis G., et al. Mitogen-actived protein kinase activation is an early event in melanoma progression. Clin. Cancer Res. 2002, 8:3728-3733.
27. Corcoran R.B., Rothenberg S.M., Hata A.N., Faber A.C., Piris A., Nazarian R.M., et al. TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma. Sci. Transl. Med. 2013, 5(96):196ra98.
28. Curtin J.A., Busam K., Pinkel D., Bastian B.C. Somatic activation of KIT in distinct subtypes of melanoma. J. Clin. Oncol. 2006, 24:4340-4346.
29. D'Angelo S., Dickson M., Kelly N., Yaqubie A., Chapman P. Switching therapy pre-emptively from vemurafenib (VEM) to ipilimumab (IPI) in patients (pts) with BRAF-mutated melanoma (MEL). Pigment Cell Melanoma Res. 2013, 26:940.
30. Dahlman K.B., Xia J., Hutchinson K., Ng C., Hucks D., Jia P., et al. BRAF(L597) mutations in melanoma are associated with sensitivity to MEK inhibitors. Cancer Discov. 2012, 2:791-797.
31. Das T., hakur M., Salangsang F., Landman A.S., Sellers W.R., Pryer N.K., Levesque M.P., et al. Modelling vemurafenib resistance in melanoma reveals a strategy to forestall drug resistance. Nature 2013, 494:251-255.
32. Daud A., Weber J.S., Sosman J.A., Kim K., Gonzalez R., Hamid O., et al. Updated overall survival (OS) results for BRF113220, a phase I-II study of dabrafenib alone versus combined dabrafenib and trametinib in patients with BRAF V600 metastatic melanoma (MM). ASCO Meet. Abstr. 2015, 33:9036.
33. Davies H., Bignell G.R., Cox C., Stephens P., Edkins S., Clegg S., et al. Mutations of the BRAF gene in human cancer. Nature 2002, 417:949-954.
34. Devitt B., Liu W., Salemi R., Wolfe R., Kelly J., Tzen C.Y., et al. Clinical outcome and pathological features associated with NRAS mutation in cutaneous melanoma. Pigment Cell Melanoma Res. 2011, 24:666-672.
35. Dougherty M.K., Muller J., Ritt D.A., Zhou M., Zhou X.Z., Copeland T.D., et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 2005, 17:215-224.
36. Dumaz N., Hayward R., Martin J., Ogilvie L., Hedley D., Curtin J.A., et al. In melanoma, RAS mutations are accompanied by switching signaling from BRAF to CRAF and disrupted cyclic AMP signaling. Cancer Res. 2006, 66:9483-9491.
37. Dummer R., Rinderknecht J., Goldinger S.M. Ultraviolet A and photosensitivity during vemurafenib therapy. N. Engl. J. Med. 2012, 366:480-481.
38. Dummer R., Robert C., Nyakas M., McArthur G.A., Kudchadkar R.R., Gomez-Roca C., et al. Initial results from a phase I, open-label, dose escalation study of the oral BRAF inhibitor LGX818 in patients with BRAF V600 mutant advanced or metastatic melanoma. ASCO Meet. Abstr. 2013, 31:9028.
39. Dummer R., Goldinger S.M., Turtschi C.P., Eggmann N.B., Michielin O., Mitchell L., et al. Vemurafenib in patients with BRAF(V600) mutation-positive melanoma with symptomatic brain metastases: final results of an open-label pilot study. Eur. J. Cancer. 2014, 50:611-621.
40. Eblen S.T., Slack-Davis J.K., Tarcsafalvi A., Parsons J.T., Weber M.J., Catling A.D. Mitogen-activated protein kinase feedback phosphorylation regulates MEK1 complex formation and activation during cellular adhesion. Mol. Cell Biol. 2004, 24:2308-2317.
41. Edlundh-Rose E., Egyhazi S., Omholt K., Mansson-Brahme E., Platz A., Hansson J., et al. NRAS and BRAF mutations in melanoma tumours in relation to clinical characteristics: a study based on mutation screening by pyrosequencing. Melanoma Res. 2006, 16:471-478.
42. Ekedahl H., Cirenajwis H., Harbst K., Carneiro A., Nielsen K., Olsson H., et al. The clinical significance of BRAF and NRAS mutations in a clinic-based metastatic melanoma cohort. Br. J. Dermatol. 2013, 169:1049-1055.
43. Ellerhorst J.A., Greene V.R., Ekmekcioglu S., Warneke C.L., Johnson M.M., Cooke C.P., et al. Clinical correlates of NRAS and BRAF mutations in primary human melanoma. Clin. Cancer Res. 2011, 17:229-235.
44. Emery C.M., Vijayendran K.G., Zipser M.C., Sawyer A.M., Niu L., Kim J.J., et al. MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proc. Natl. Acad. Sci. U. S. A. 2009, 106:20411-20416.
45. Falchook G.S., Long G.V., Kurzrock R., Kim K.B., Arkenau T.H., Brown M.P., et al. Dabrafenib in patients with melanoma, untreated brain metastases, and other solid tumours: a phase 1 dose-escalation trial. Lancet 2012, 379:1893-1901.
46. Falchook G.S., Lewis K.D., Infante J.R., Gordon M.S., Vogelzang N.J., DeMarini D.J., et al. Activity of the oral MEK inhibitor trametinib in patients with advanced melanoma: a phase 1 dose-escalation trial. Lancet Oncol. 2012, 13:782-789.
47. Flaherty K.T., Puzanov I., Kim K.B., Ribas A., McArthur G.A., Sosman J.A., et al. Inhibition of mutated, activated BRAF in metastatic melanoma. N. Engl. J. Med. 2010, 363:809-819.
48. Flaherty K.T., Robert C., Hersey P., Nathan P., Garbe C., Milhem M., et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N. Engl. J. Med. 2012, 367:107-114.
49. Flaherty K.T., Infante J.R., Daud A., Gonzalez R., Kefford R.F., Sosman J., et al. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N. Engl. J. Med. 2012, 367:1694-1703.
50. Frederick D.T., Piris A., Cogdill A.P., Cooper Z.A., Lezcano C., Ferrone C.R., et al. BRAF inhibition is associated with enhanced melanoma antigen expression and a more favorable tumor microenvironment in patients with metastatic melanoma. Clin. Cancer Res. 2013, 19:1225-1231.
51. Garnett M.J., Rana S., Paterson H., Barford D., Marais R. Wild-type and mutant B-RAF activate C-RAF through distinct mechanisms involving heterodimerization. Mol. Cell 2005, 20:963-969.
52. Genomic Classification of Cutaneous Melanoma. Cell. 2015;161:1681-96.
53. Gilmartin A.G., Bleam M.R., Groy A., Moss K.G., Minthorn E.A., Kulkarni S.G., et al. GSK1120212 (JTP-74057) is an inhibitor of MEK activity and activation with favorable pharmacokinetic properties for sustained in vivo pathway inhibition. Clin. Cancer Res. 2011, 17:989-1000.
54. Girotti M.R., Pedersen M., Sanchez-Laorden B., Viros A., Turajlic S., Niculescu-Duvaz D., et al. Inhibiting EGF receptor or SRC family kinase signaling overcomes BRAF inhibitor resistance in melanoma. Cancer Discov. 2013, 3:158-167.
55. Gopal Y.N., Rizos H., Chen G., Deng W., Frederick D.T., Cooper Z.A., et al. Inhibition of mTORC1/2 overcomes resistance to MAPK pathway inhibitors mediated by PGC1alpha and oxidative phosphorylation in melanoma. Cancer Res. 2014, 74:7037-7047.
56. Gowrishankar K., Snoyman S., Pupo G.M., Becker T.M., Kefford R.F., Rizos H. Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J. Invest. Dermatol. 2012, 132:1850-1859.
57. Gramza A.W., Corless C.L., Heinrich M.C. Resistance to tyrosine kinase inhibitors in gastrointestinal stromal tumors. Clin. Cancer Res. 2009, 15:7510-7518.
58. Greger J.G., Eastman S.D., Zhang V., Bleam M.R., Hughes A.M., Smitheman K.N., et al. Combinations of BRAF, MEK, and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol. Cancer Ther. 2012, 11:909-920.
59. Guo J., Si L., Kong Y., Flaherty K.T., Xu X., Zhu Y., Phase I.I., et al. open-label, single-arm trial of imatinib mesylate in patients with metastatic melanoma harboring c-Kit mutation or amplification. J. Clin. Oncol. 2011, 29:2904-2909.
60. Halaban R., Zhang W., Bacchiocchi A., Cheng E., Parisi F., Ariyan S., et al. PLX4032, a selective BRAF(V600E) kinase inhibitor, activates the ERK pathway and enhances cell migration and proliferation of BRAF melanoma cells. Pigment Cell Melanoma Res. 2010, 23:190-200.
61. Hammerman P.S., Janne P.A., Johnson B.E. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer. Clin. Cancer Res. 2009, 15:7502-7509.
62. Hanafusa H., Torii S., Yasunaga T., Nishida E. Sprouty1 and Sprouty2 provide a control mechanism for the Ras/MAPK signalling pathway. Nat. Cell Biol. 2002, 4:850-858.
63. Haq R., Shoag J., Andreu-Perez P., Yokoyama S., Edelman H., Rowe G.C., et al. Oncogenic BRAF regulates oxidative metabolism via PGC1alpha and MITF. Cancer Cell 2013, 23:302-315.
64. Hartsough E.J., Basile K.J., Aplin A.E. Beneficial effects of RAF inhibitor in mutant BRAF splice variant-expressing melanoma. Mol. Cancer Res. 2014, 12:795-802.
65. Hatzivassiliou G., Song K., Yen I., Brandhuber B.J., Anderson D.J., Alvarado R., et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 2010, 464:431-435.
66. Hauschild A., Grob J.J., Demidov L.V., 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, 380:358-365.
67. Heidorn S.J., Milagre C., Whittaker S., Nourry A., Niculescu-Duvas I., Dhomen N. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell 2010, 140:209-221.
68. Hodi F.S., O'Day S.J., McDermott D.F., Weber R.W., Sosman J.A., Haanen J.B., et al. Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010, 363:711-723.
69. Hodi F.S., Corless C.L., Giobbie-Hurder A., Fletcher J.A., Zhu M., Marino-Enriquez A., et al. Imatinib for melanomas harboring mutationally activated or amplified KIT arising on mucosal, acral, and chronically sun-damaged skin. J. Clin. Oncol. 2013, 31:3182-3190.
70. Hodis E., Watson I.R., Kryukov G.V., Arold S.T., Imielinski M., Theurillat J.P., et al. A landscape of driver mutations in melanoma. Cell 2012, 150:251-263.
71. Hu-Lieskovan S., Mok S., Homet Moreno B., Tsoi J., Robert L., Goedert L., et al. Improved antitumor activity of immunotherapy with BRAF and MEK inhibitors in BRAF(V600E) melanoma. Sci. Transl. Med. 2015, 7:279ra41.
72. Hutchinson K.E., Lipson D., Stephens P.J., Otto G., Lehmann B.D., Lyle P.L., et al. BRAF fusions define a distinct molecular subset of melanomas with potential sensitivity to MEK inhibition. Clinical Cancer Res. 2013, 19:6696-6702.
73. Jakob J.A., Bassett R.L.J., r, Ng C.S., Curry J.L., Joseph R.W., Alvarado G.C., et al. NRAS mutation status is an independent prognostic factor in metastatic melanoma. Cancer 2012, 118:4014-4023.
74. Johannessen C.M., Boehm J.S., Kim S.Y., Thomas S.R., Wardwell L., Johnson L.A., et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 2010, 468:968-972.
75. Johnson D.B., Flaherty K.T., Weber J.S., Infante J.R., Kim K.B., Kefford R.F., et al. Combined BRAF (Dabrafenib) and MEK inhibition (Trametinib) in patients with BRAFV600-mutant melanoma experiencing progression with single-agent BRAF inhibitor. J. Clin. Oncol. 2014, 32:3697-3704.
76. Johnson D.B., Menzies A.M., Zimmer L., Eroglu Z., Ye F., Zhao S., et al. BRAF inhibitor acquired resistance: A multicenter meta-analysis of the spectrum and clinical implications of resistance mechanisms. ASCO Meet. Abstr. 2015, 33:9008.
77. Jubb A.M., Ribas A., Sosman J.A., McArthur G.A., Yan Y., Rost S., et al. Impact of MET expression on outcome in BRAF(V600E/K) advanced melanoma. Histopathology. 2013, 63:351-361.
78. Katz M., Amit I., Yarden Y. Regulation of MAPKs by growth factors and receptor tyrosine kinases. Biochim Biophys. Acta. 2007, 1773:1161-1176.
79. Kefford R.F., Maio M., Arance A., Nathan P., Blank C., Avril M.F., et al. Vemurafenib in metastatic melanoma patients with brain metastases: an open-label, single-arm, phase 2, multicenter study. Pigment Cell Melanoma Res. 2013, 26:965.
80. Kim K.B., Kefford R., Pavlick A.C., Infante J.R., Ribas A., Sosman J.A. 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. 2013, 31:482-489.
81. King A.J., Arnone M.R., Bleam M.R., Moss K.G., Yang J., Fedorowicz K.E., et al. Dabrafenib; preclinical characterization, increased efficacy when combined with trametinib, while BRAF/MEK tool combination reduced skin lesions. PLoS One 2013, 8:e67583.
82. Klein O., Clements A., Menzies A.M., O'Toole S., Kefford R.F., Long G.V. BRAF inhibitor activity in V600R metastatic melanoma. Eur. J. Cancer 2013, 49:1073-1079.
83. Kohno M., Pouyssegur J. Targeting the ERK signaling pathway in cancer therapy. Ann. Med. 2006, 38:200-211.
84. Kortylewski M., Heinrich P.C., Kauffmann M.E., Bohm M., MacKiewicz A., Behrmann I. Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells. Biochem. J. 2001, 357:297-303.
85. Larkin J., Ascierto P.A., Dreno B., Atkinson V., Liszkay G., Maio M., et al. Combined vemurafenib and cobimetinib in BRAF-mutated melanoma. N. Engl. J. Med. 2014, 371:1867-1876.
86. Larkin J., Del V., ecchio M., Ascierto P.A., Krajsova I., Schachter J., Neyns B., et al. Vemurafenib in patients with BRAF(V600) mutated metastatic melanoma: an open-label, multicentre, safety study. Lancet Oncol. 2014, 15:436-444.
87. Lezcano C., Lee C.W., Larson A.R., Menzies A.M., Kefford R.F., Thompson J.F., et al. Evaluation of stromal HGF immunoreactivity as a biomarker for melanoma response to RAF inhibitors. Mod. Pathol. 2014, 27:1193-1202.
88. Li G., Schaider H., Satyamoorthy K., Hanakawa Y., Hashimoto K., Herlyn M. Downregulation of E-cadherin and Desmoglein 1 by autocrine hepatocyte growth factor during melanoma development. Oncogene 2001, 20:8125-8135.
89. Li X., Huang Y., Jiang J., Frank S.J. ERK-dependent threonine phosphorylation of EGF receptor modulates receptor downregulation and signaling. Cell. Signal. 2008, 20:2145-2155.
90. Lin L., Sabnis A.J., Chan E., Olivas V., Cade L., Pazarentzos E., et al. The Hippo effector YAP promotes resistance to RAF- and MEK-targeted cancer therapies. Nat. Genet. 2015, 47:250-256.
91. Lito P., Pratilas C., hristine A., Joseph E., ric W., 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, 22:668-682.
92. Little A.S., Balmanno K., Sale M.J., Newman S., Dry J.R., Hampson M., et al. Amplification of the driving oncogene, KRAS or BRAF, underpins acquired resistance to MEK1/2 inhibitors in colorectal cancer cells. Sci. Signal. 2011, 4:ra17.
93. Liu W., Kelly J.W., Trivett M., Murray W.K., Dowling J.P., Wolfe R., et al. Distinct clinical and pathological features are associated with the BRAF(T1799A(V600E)) mutation in primary melanoma. J. Invest. Dermatol. 2007, 127:900-905.
94. Liu L., Mayes P.A., Eastman S., Shi H., Yadavilli S., Zhang T., The B.R.A.F., and, et al. MEK inhibitors dabrafenib and trametinib: effects on immune function and in combination with immunomodulatory antibodies targeting PD-1, PD-L1, and CTLA-4. Clin. Cancer Res. 2015, 21:1639-1651.
95. Long G.V., Menzies A.M., Nagrial A.M., Haydu L.E., Hamilton A.L., Mann G.J., et al. Prognostic and clinicopathologic associations of oncogenic BRAF in metastatic melanoma. J. Clin. Oncol. 2011, 29:1239-1246.
96. Long G.V., Trefzer U., Davies M.A., Kefford R.F., Ascierto P.A., Chapman P.B., et al. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012, 13:1087-1095.
97. Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de Braud F., Larkin J., et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N. Engl. J. Med. 2014, 371:1877-1888.
98. Long G.V., Fung C., Menzies A.M., Pupo G.M., Carlino M.S., Hyman J. Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma. Nat. Commun. 2014, 5:5694.
99. Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de B., raud F., Larkin J., et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015.
100. Long G.V., Stroyakovskiy D., Gogas H., Levchenko E., de B., raud F., Larkin J., et al. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet 2015, 386:444-451.
101. Lyle M., Long G.V. Diagnosis and treatment of KIT-mutant metastatic melanoma. J. Clin. Oncol. 2013, 31:3176-3181.
102. Mandala M., Merelli B., Massi D. Nras in melanoma: targeting the undruggable target. Crit. Rev. Oncol. Hematol. 2014, 92:107-122.
103. Mann G.J., Pupo G.M., Campain A.E., Carter C.D., Schramm S.J., Pianova S., et al. BRAF mutation, NRAS mutation, and the absence of an immune-related expressed gene profile predict poor outcome in patients with stage III Melanoma. J Invest. Dermatol. 2013, 133:509-517.
104. Mar V.J., Wong S.Q., Logan A., Nguyen T., Cebon J., Kelly J.W., et al. Clinical and pathological associations of the activating RAC1 P29S mutation in primary cutaneous melanoma. Pigment Cell Melanoma Res. 2014, 27:1117-1125.
105. Massi D., Brusa D., Merelli B., Falcone C., Xue G., Carobbio A., et al. The status of PD-L1 and tumor-infiltrating immune cells predict resistance and poor prognosis in BRAFi-treated melanoma patients harboring mutant BRAFV 600. Ann. Oncol. 2015.
106. McArthur G.A., Chapman P.B., Robert C., Larkin J., Haanen J.B., Dummer R., et al. 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. 2014, 15:323-332.
107. Menzies A.M., Haydu L.E., Visintin L., Carlino M.S., Howle J.R., Thompson J.F., et al. Distinguishing clinicopathologic features of patients with V600E and V600K BRAF-mutant metastatic melanoma. Clin. Cancer Res. 2012, 18:3242-3249.
108. Menzies A.M., Kefford R.F., Long G.V. Paradoxical oncogenesis: are all BRAF inhibitors equal?. Pigment Cell Melanoma Res. 2013, 26:611-615.
109. Menzies A.M., Yeh I., Botton T., Bastian B.C., Scolyer R.A., Long G.V. Clinical activity of the MEK inhibitor trametinib in metastatic melanoma containing BRAF kinase fusion. Pigment Cell Melanoma Res. 2015.
110. Menzies A.M., Ashworth M.T., Swann S., Kefford R.F., Flaherty K., Weber J., et al. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann. Oncol. 2015, 26:415-421.
111. Montagut C., Sharma S.V., Shioda T., McDermott U., Ulman M., Ulkus L.E., et al. Elevated CRAF as a potential mechanism of acquired resistance to BRAF inhibition in melanoma. Cancer Res. 2008, 68:4853-4861.
112. Moreau S., Saiag P., Aegerter P., Bosset D., Longvert C., Helias-Rodzewicz Z., et al. Prognostic value of BRAF(V(6)(0)(0)) mutations in melanoma patients after resection of metastatic lymph nodes. Ann. Surg. Oncol. 2012, 19:4314-4321.
113. Moriceau G., Hugo W., Hong A., Shi H., Kong X., Yu C.C., et al. Tunable-Combinatorial Mechanisms of Acquired Resistance Limit the Efficacy of BRAF/MEK Cotargeting but Result in Melanoma Drug Addiction. Cancer Cell 2015.
114. Nathanson K.L., Martin A.M., Wubbenhorst B., Greshock J., Letrero R., D'Andrea K., et al. Tumor genetic analyses of patients with metastatic melanoma treated with the BRAF inhibitor dabrafenib (GSK2118436). Clin. Cancer Res. 2013, 19:4868-4878.
115. Nazarian R., Shi H., Wang Q., Kong X., Koya R.C., Lee H., et al. Melanomas acquire resistance to B-RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010, 468:973-977.
116. Nissan M.H., Pratilas C.A., Jones A.M., Ramirez R., Won H., Liu C., et al. Loss of NF1 in cutaneous Melanoma Is associated with RAS activation and MEK dependence. Cancer Res. 2014, 74:2340-2350.
117. Noble C., Mercer K., Hussain J., Carragher L., Giblett S., Hayward R., et al. CRAF autophosphorylation of serine 621 is required to prevent its proteasome-mediated degradation. Mol. Cell 2008, 31:862-872.
118. Paraiso K.H., Fedorenko I.V., Cantini L.P., Munko A.C., Hall M., Sondak V.K., et al. Recovery of phospho-ERK activity allows melanoma cells to escape from BRAF inhibitor therapy. Br. J. Cancer 2010, 102:1724-1730.
119. Parmenter T.J., Kleinschmidt M., Kinross K.M., Bond S.T., Li J., Kaadige M.R., et al. Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. Cancer Discov. 2014, 4:423-433.
120. Pedersen M., Viros A., Cook M., Marais R. (G12D) NRAS and kinase-dead BRAF cooperate to drive naevogenesis and melanomagenesis. Pigment Cell Melanoma Res. 2014, 27:1162-1166.
121. Platz A., Egyhazi S., Ringborg U., Hansson J. Human cutaneous melanoma; a review of NRAS and BRAF mutation frequencies in relation to histogenetic subclass and body site. Mol. Oncol. 2008, 1:395-405.
122. Porcelli L., Guida G., Tommasi S., Guida M., Azzariti A. Metastatic melanoma cells with BRAF G469A mutation: nab-paclitaxel better than vemurafenib?. Cancer Chemother. Pharmacol. 2015, 76:433-438.
123. Poulikakos P.I., Zhang C., Bollag G., Shokat K.M., Rosen N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 2010, 464:427-430.
124. Poulikakos P.I., 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, 480:387-390.
125. Prahallad A., Sun C., Huang S., Di N., icolantonio F., Salazar R., Zecchin D., et al. Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR. Nature 2012, 483:100-103.
126. Ribas A., Gonzalez R., Pavlick A., Hamid O., Gajewski T.F., Daud A., et al. Combination of vemurafenib and cobimetinib in patients with advanced BRAFV600-mutated melanoma: a phase 1b study. Lancet Oncol. 2014, 15:954-965.
127. Ribas A., Puzanov I., Dummer R., Schadendorf D., Hamid O., Robert C., et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. 2015, 16:908-918.
128. Ribas A., Butler M., Lutzky J., Lawrence D.P., Robert C., Miller W., et al. Phase I study combining anti-PD-L1 (MEDI4736) with BRAF (dabrafenib) and/or MEK (trametinib) inhibitors in advanced melanoma. ASCO Meet. Abstr. 2015, 33:3003.
129. Rizos H., Menzies A.M., Pupo G.M., Carlino M.S., Fung C., Hyman J., et al. BRAF Inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin. Cancer Res. 2014, 20:1965-1977.
130. Robert C., Thomas L., Bondarenko I., O'Day S.M.D., JWG, arbe C., et al. Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 2011, 364:2517-2526.
131. Robert C., Karaszewska B., Schachter J., Rutkowski P., Mackiewicz A., Stroiakovski D., et al. Improved overall survival in melanoma with combined dabrafenib and trametinib. N. Engl. J. Med. 2015, 372:30-39.
132. Robert C., Long G.V., Brady B., Dutriaux C., Maio M., Mortier L., et al. Nivolumab in previously untreated melanoma without BRAF mutation. N. Engl. J. Med. 2015, 372:320-330.
133. Robert C., Schachter J., Long G.V., Arance A., Grob J.J., Mortier L., et al. Pembrolizumab versus ipilimumab in advanced Melanoma. N. Engl. J. Med. 2015, 372:2521-2532.
134. Romano E., Pradervand S., Paillusson A., Weber J., Harshman K., Muehlethaler K., et al. Identification of multiple mechanisms of resistance to vemurafenib in a patient with BRAFV600E-mutated cutaneous melanoma successfully rechallenged after progression. Clin. Cancer Res. 2013, 19:5749-5757.
135. Rutkowski P., Gos A., Jurkowska M., Switaj T., Dziewirski W., Zdzienicki M., et al. Molecular alterations in clinical stage III cutaneous melanoma: correlation with clinicopathological features and patient outcome. Oncol. Lett. 2014, 8:47-54.
136. Salton M., Kasprzak W.K., Voss T., Shapiro B.A., Poulikakos P.I., Misteli T. Inhibition of vemurafenib-resistant melanoma by interference with pre-mRNA splicing. Nat. Commun. 2015, 6:7103.
137. Schadendorf D., Amonkar M.M., Stroyakovskiy D., Levchenko E., Gogas H., de B., raud F., et al. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur. J. Cancer 2015, 51:833-840.
138. Scholtens A., Geukes F., oppen M.H., Blank C.U., van T., hienen J.V., van T., interen H., Haanen J.B. Vemurafenib for BRAF V600 mutated advanced melanoma: results of treatment beyond progression. Eur. J. Cancer 2015, 51:642-652.
139. Sensi M., Nicolini G., Petti C., Bersani I., Lozupone F., Molla A., et al. Mutually exclusive NRASQ61R and BRAFV600E mutations at the single-cell level in the same human melanoma. Oncogene 2006, 25:3357-3364.
140. Shi H., Kong X., Ribas A., Lo R.S. Combinatorial treatments that overcome PDGFRbeta-driven resistance of melanoma cells to V600EB-RAF inhibition. Cancer Res. 2011, 71:5067-5074.
141. Shi H., Moriceau G., Kong X., Koya R.C., Nazarian R., Pupo G.M., et al. Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors. Cancer Discov 2012, 2:414-424.
142. Shi H., Moriceau G., Kong X., Lee M.-K., Lee H., Koya R.C., et al. Melanoma whole-exome sequencing identifies V600EB-RAF amplification-mediated acquired B-RAF inhibitor resistance. Nat. Commun. 2012, 3:724.
143. Shi H., Hugo W., Kong X., Hong A., Koya R.C., Moriceau G., et al. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014, 4:80-93.
144. Shi H., Hong A., Kong X., Koya R.C., Song C., Moriceau G., et al. A novel AKT1 mutant amplifies an adaptive melanoma response to BRAF inhibition. Cancer Discov. 2014, 4:69-79.
145. Simon R., Richter J., Wagner U., Fijan A., Bruderer J., Schmid U., et al. High-throughput tissue microarray analysis of 3p25 (RAF1) and 8p12 (FGFR1) copy number alterations in urinary bladder cancer. Cancer Res. 2001, 61:4514-4519.
146. Sosman J.A., Kim K.B., Schuchter L., Gonzalez R., Pavlick A.C., Weber J.S., et al. Survival in BRAF V600-mutant advanced melanoma treated with vemurafenib. N. Engl. J. Med. 2012, 366:707-714.
147. Sosman J.A., Daud A., Weber J.S., Kim K., Kefford R., Flaherty K., et al. BRAF inhibitor (BRAFi) dabrafenib in combination with the MEK1/2 inhibitor (MEKi) trametinib in BRAFi-naive and BRAFi-resistant patients (pts) with BRAF mutation-positive metastatic melanoma (MM). ASCO Meet. Abstr. 2013, 31:9005.
148. Stones C.J., Kim J.E., Joseph W.R., Leung E., Marshall E.S., Finlay G.J., et al. Comparison of responses of human melanoma cell lines to MEK and BRAF inhibitors. Front. Genet. 2013, 4:66.
149. Straussman R., Morikawa T., Shee K., Barzily-Rokni M., Qian Z.R., Du J., et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature 2012, 487:500-504.
150. Sturm O.E., Orton R., Grindlay J., Birtwistle M., Vyshemirsky V., Gilbert D., et al. The mammalian MAPK/ERK pathway exhibits properties of a negative feedback amplifier. Sci. Signal. 2010, 3:ra90.
151. Su F., Viros A., Milagre C., Trunzer K., Bollag G., Spleiss O., et al. RAS mutations in cutaneous squamous-cell carcinomas in patients treated with BRAF inhibitors. N. Engl. J. Med. 2012, 366:207-215.
152. Su F., Bradley W.D., Wang Q., Yang H., Xu L., Higgins B., et al. Resistance to selective BRAF inhibition can be mediated by modest upstream pathway activation. Cancer Res. 2012, 72:969-978.
153. Sullivan R.J., Weber J.S., Patel S.P., Dummer R., Miller W.H., Cosgrove D., et al A phase Ib/II study of BRAF inhibitor (BRAFi) encorafenib (ENCO) plus MEK inhibitor (MEKi) binimetinib (BINI) in cutaneous melanoma patients naive to BRAFi treatment. ASCO Meet. Abstr. 2015, 33:9007.
154. Sun C., Wang L., Huang S., Heynen G.J., Prahallad A., Robert C., et al. Reversible and adaptive resistance to BRAF(V600E) inhibition in melanoma. Nature 2014, 508:118-122.
155. Todd J.R., Scurr L.L., Becker T.M., Kefford R.F., Rizos H. The MAPK pathway functions as a redundant survival signal that reinforces the PI3K cascade in c-Kit mutant melanoma. Oncogene 2014, 33:236-245.
156. Trunzer K., Pavlick A.C., Schuchter L., Gonzalez R., McArthur G.A., Hutson T.E., et al. Pharmacodynamic effects and mechanisms of resistance to vemurafenib in patients with metastatic melanoma. J. Clin. Oncol. 2013, 31:1767-1774.
157. Tsavachidou D., Coleman M.L., Athanasiadis G., Li S., Licht J.D., Olson M.F., et al. SPRY2 is an inhibitor of the ras/extracellular signal-regulated kinase pathway in melanocytes and melanoma cells with wild-type BRAF but not with the V599E mutant. Cancer Res. 2004, 64:5556-5559.
158. Ugurel S., Thirumaran R.K., Bloethner S., Gast A., Sucker A., Mueller-Berghaus J., et al. B-RAF and N-RAS mutations are preserved during short time in vitro propagation and differentially impact prognosis. PLoS One 2007, 2:e236.
159. Van R., aamsdonk C.D., Bezrookove V., Green G., Bauer J., Gaugler L., O'Brien J.M., et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 2009, 457:599-602.
160. Van A., llen E.M., Wagle N., Sucker A., Treacy D.J., Johannessen C.M., Goetz E.M., et al. The genetic landscape of clinical resistance to RAF inhibition in metastatic melanoma. Cancer Discov. 2014, 4:94-109.
161. Villanueva J., Vultur A., Lee J.T., Somasundaram R., Fukunaga-Kalabis M., Cipolla A.K., 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 2010, 18:683-695.
162. Villanueva J., Infante J.R., Krepler C., Reyes-Uribe P., Samanta M., Chen H.Y., et al. Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell Rep. 2013, 4:1090-1099.
163. Viros A., Fridlyand J., Bauer J., Lasithiotakis K., Garbe C., Pinkel D., et al. Improving melanoma classification by integrating genetic and morphologic features. PLoS Med. 2008, 5:e120.
164. Wagenaar T.R., Ma L., Roscoe B., Park S.M., Bolon D.N., Green M.R. Resistance to vemurafenib resulting from a novel mutation in the BRAFV600E kinase domain. Pigment Cell Melanoma Res. 2014, 27:124-133.
165. Wagle N., Emery C., Berger M.F., Davis M.J., Sawyer A., Pochanard P., et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 2011, 29:3085-3096.
166. Wagle N., Van Allen E.M., Treacy D.J., Frederick D.T., Cooper Z.A., Taylor-Weiner A., et al. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov. 2014, 4:61-68.
167. Wan P.T.C., Garnett M.J., Roe S.M., Lee S., Niculescu-Duvaz D., Good V.M., et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell 2004, 116:855-867.
168. Wang J., Huang S.K., Marzese D.M., Hsu S.C., Kawas N.P., Chong K.K., et al. Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas. J. Invest. Dermatol. 2015, 135:532-541.
169. Warburg O. On the origin of cancer cells. Science 1956, 123:309-314.
170. Watson I.R., Li L., Cabeceiras P.K., Mahdavi M., Gutschner T., Genovese G., et al. The RAC1 P29S Hotspot Mutation in Melanoma Confers Resistance to Pharmacological Inhibition of RAF. Cancer Res. 2014, 74:4845-4852.
171. Weber J.S., D'Angelo S.P., Minor D., Hodi F.S., Gutzmer R., Neyns B., et al. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2015, 16:375-384.
172. Whittaker S.R., Theurillat J.P., Van A., llen E., Wagle N., Hsiao J., Cowley G.S., et al. A genome-scale RNA interference screen implicates NF1 loss in resistance to RAF inhibition. Cancer Discov. 2013, 3:350-362.
173. Widlund H.R., Fisher D.E. Microphthalamia-associated transcription factor: a critical regulator of pigment cell development and survival. Oncogene 2003, 22:3035-3041.
174. Wilmott J.S., Tembe V., Howle J.R., Sharma R., Thompson J.F., Rizos H., et al. Intratumoral molecular heterogeneity in a BRAF-mutant, BRAF inhibitor-resistant melanoma: a case illustrating the challenges for personalized medicine. Mol. Cancer Ther. 2012, 11:2704-2708.
175. Wilmott J.S., Long G.V., Howle J.R., Haydu L.E., Sharma R.N., Thompson J.F., et al. Selective BRAF inhibitors induce marked T-cell infiltration into human metastatic melanoma. Clin. Cancer Res. 2012, 18:1386-1394.
176. Woods D., Cherwinski H., Venetsanakos E., Bhat A., Gysin S., Humbert M., et al. Induction of beta3-integrin gene expression by sustained activation of the Ras-regulated Raf-MEK-extracellular signal-regulated kinase signaling pathway. Mol. Cell Biol. 2001, 21:3192-3205.
177. Zimmer L., Hillen U., Livingstone E., Lacouture M.E., Busam K., Carvajal R.D., et al. Atypical melanocytic proliferations and new primary melanomas in patients with advanced melanoma undergoing selective BRAF inhibition. J. Clin. Oncol. 2012, 30:2375-2383.