Current Therapy for Advanced Melanoma and a Look at Future Signaling Pathways to Target
Main Article Content
Keywords
melanoma, vemurafanib, notch, wnt, hedgehog, hippo,
Abstract
Metastatic melanoma is a heterogeneous tumor of the skin derived from melanocytes notorious for its resistance to various forms of systemic therapy. Many different types of monotherapies and combination therapies have been developed in recent years, each with their own setbacks, and drawbacks. This review article will provide an overview of current FDA approved drug therapies for stage III and IV metastatic melanoma, key signaling pathways they target, and mechanisms of drug resistance. This paper will then look at future therapy for metastatic melanoma with a particular focus on targeted therapy on embryonic and evolutionarily conserved pathways in metastatic melanoma, including notch, wnt, hippo, hedgehog signaling, among others.
References
1. Tang T, Eldabaje R, Yang L. Current Status of Biological Therapies for the
Treatment of Metastatic Melanoma. Anticancer Res. 2016 Jul;36(7):3229-41. Review.
PubMed [citation] PMID: 27354579
2. Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, Lok HC,
Sahni S, Lane DJ, Richardson DR. Roads to melanoma: Key pathways and emerging
players in melanoma progression and oncogenic signaling. Biochim Biophys Acta.
2016 Apr;1863(4):770-84. doi: 10.1016/j.bbamcr.2016.01.025. Epub 2016 Feb 1.
Review. PubMed [citation] PMID: 26844774
3. 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, van Baren N, Long GV, Ribas A, Lo RS. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93. doi:
10.1158/2159-8290.CD-13-0642. Epub 2013 Nov 21. PubMed [citation] PMID: 24265155,PMCID: PMC3936420
4. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. doi: 10.1056/NEJMoa1709684. Epub 2017 Sep 11.
5. Fox MC, Lao CD, Schwartz JL, Frohm ML, Bichakjian CK, Johnson TM. Management
options for metastatic melanoma in the era of novel therapies: a primer for the
practicing dermatologist: part I: Management of stage III disease. J Am Acad
Dermatol. 2013 Jan;68(1):1.e1-9; quiz 10-12. doi: 10.1016/j.jaad.2012.09.040.
PubMed [citation] PMID: 23244383
6. Fox MC, Lao CD, Schwartz JL, Frohm ML, Bichakjian CK, Johnson TM. Management
options for metastatic melanoma in the era of novel therapies: a primer for the
practicing dermatologist: part II: Management of stage IV disease. J Am Acad
Dermatol. 2013 Jan;68(1):13.e1-13; quiz 26-8. doi: 10.1016/j.jaad.2012.09.041.
PubMed [citation] PMID: 23244384
7. O'Sullivan Coyne G, Madan RA, Gulley JL. Nivolumab: promising survival signal
coupled with limited toxicity raises expectations. J Clin Oncol. 2014 Apr
1;32(10):986-8. doi: 10.1200/JCO.2013.54.5996. Epub 2014 Mar 3. No abstract
available. PubMed [citation] PMID: 24590655
8. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R,
Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J,
Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C,
Quirt I, Clark JI, et al. Improved survival with ipilimumab in patients with
metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi:
10.1056/NEJMoa1003466. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep
23;363(13):1290. PubMed [citation] PMID: 20525992, PMCID: PMC3549297
Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L.
Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol
Res. 2007 Oct;56(4):275-87. Epub 2007 Aug 9. Review. PubMed [citation] PMID:
17897837
9. Weber J. Ipilimumab: controversies in its development, utility and autoimmune
adverse events. Cancer Immunol Immunother. 2009 May;58(5):823-30. doi:
10.1007/s00262-008-0653-8. Epub 2009 Feb 6. Review. PubMed [citation] PMID:
19198837
10. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer
immunotherapy. Cancer Control. 2014 Jul;21(3):231-7. Review. PubMed [citation]
PMID: 24955707
11. Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: latest evidence and
clinical potential. Ther Adv Med Oncol. 2015 Mar;7(2):97-106. doi:
10.1177/1758834014567469. Review. PubMed [citation] PMID: 25755682, PMCID:
PMC4346215
12. Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L.
Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol
Res. 2007 Oct;56(4):275-87. Epub 2007 Aug 9. Review. PubMed [citation] PMID:
17897837
13. Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of
medical treatment in melanoma: current status and future prospects. Oncologist.
2011;16(1):5-24. doi: 10.1634/theoncologist.2010-0190. Epub 2011 Jan 6. Review.
PubMed [citation] PMID: 21212434, PMCID: PMC3228046
14. Atkinson V. Medical management of malignant melanoma. Aust Prescr. 2015
Jun;38(3):74-8. Epub 2015 Mar 11. Review. PubMed [citation] PMID: 26648623,
PMCID: PMC4653963
15. 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, et al. Mutations of
the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-54. Epub 2002
Jun 9. PubMed [citation] PMID: 12068308
16. 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, et al.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J
Med. 2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5.
PubMed [citation] PMID: 21639808, PMCID: PMC3549296
17. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P,
Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C,
Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman
V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,
open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul
28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. PubMed
[citation] PMID: 22735384
18. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee
RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in
metastatic melanoma. N Engl J Med. 2010 Aug 26;363(9):809-19. doi:
10.1056/NEJMoa1002011. PubMed [citation] PMID: 20818844, PMCID: PMC3724529
19. 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, van Baren
N, Long GV, Ribas A, Lo RS. Acquired resistance and clonal evolution in melanoma
during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93. doi:
10.1158/2159-8290.CD-13-0642. Epub 2013 Nov 21. PubMed [citation] PMID: 24265155,
PMCID: PMC3936420
20. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D,
Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K,
Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P,
Ribas A, Martin AM, Sun P, et al. Improved overall survival in melanoma with
combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi:
10.1056/NEJMoa1412690. Epub 2014 Nov 16. PubMed [citation] PMID: 25399551
21. Smalley KS, Fedorenko IV. Inhibition of BRAF and BRAF+MEK drives a metastatic
switch in melanoma. Mol Cell Oncol. 2015 Mar 19;2(4):e1008291. doi:
10.1080/23723556.2015.1008291. eCollection 2015 Oct-Dec. PubMed [citation] PMID:
27308505, PMCID: PMC4905349
22. 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, Millward
M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko
N, Mohr P, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone
in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. doi:
10.1056/NEJMoa1406037. Epub 2014 Sep 29. PubMed [citation] PMID: 25265492
23. Wehrle-Haller B. The role of Kit-ligand in melanocyte development and epidermal
homeostasis. Pigment Cell Res. 2003 Jun;16(3):287-96. Review. PubMed [citation]
PMID: 12753403
24. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas
KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N,
Vemula S, Bouvier N, Bastian BC, Schwartz GK. KIT as a therapeutic target in
metastatic melanoma. JAMA. 2011 Jun 8;305(22):2327-34. doi:
10.1001/jama.2011.746. PubMed [citation] PMID: 21642685, PMCID: PMC3986039
25. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X,
Cui C, Chi Z, Li S, Han M, Mao L, Lin X, Du N, Zhang X, Li J, Wang B, Qin S.
Phase II, open-label, single-arm trial of imatinib mesylate in patients with
metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011
Jul 20;29(21):2904-9. doi: 10.1200/JCO.2010.33.9275. Epub 2011 Jun 20. PubMed
[citation] PMID: 21690468
26. Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B,
Glaspy JA, Comin-Anduix B, Mischel PS, Lo RS, Ribas A. Reversing melanoma
cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway.
PLoS One. 2011;6(12):e28973. doi: 10.1371/journal.pone.0028973. Epub 2011 Dec 14.
PubMed [citation] PMID: 22194965, PMCID: PMC3237573
27. Penna I, Molla A, Grazia G, Cleris L, Nicolini G, Perrone F, Picciani B, Del
Vecchio M, de Braud F, Mortarini R, Anichini A. Primary cross-resistance to
BRAFV600E-, MEK1/2- and PI3K/mTOR-specific inhibitors in BRAF-mutant melanoma
cells counteracted by dual pathway blockade. Oncotarget. 2016 Jan
26;7(4):3947-65. doi: 10.18632/oncotarget.6600. PubMed [citation] PMID: 26678033,
PMCID: PMC4826182
28. Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, Lok HC,
Sahni S, Lane DJ, Richardson DR. Roads to melanoma: Key pathways and emerging
players in melanoma progression and oncogenic signaling. Biochim Biophys Acta.
2016 Apr;1863(4):770-84. doi: 10.1016/j.bbamcr.2016.01.025. Epub 2016 Feb 1.
Review. PubMed [citation] PMID: 26844774
29. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003 May
19;22(20):3113-22. Review. PubMed [citation] PMID: 12789288
30. Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP. Loss of PTEN
promotes tumor development in malignant melanoma. Cancer Res. 2003 Jun
1;63(11):2881-90. PubMed [citation] PMID: 12782594
31. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr, You MJ,
DePinho RA, McMahon M, Bosenberg M. Braf(V600E) cooperates with Pten loss to
induce metastatic melanoma. Nat Genet. 2009 May;41(5):544-52. doi:
10.1038/ng.356. Epub 2009 Mar 12. PubMed [citation] PMID: 19282848, PMCID:
PMC2705918
32. Pinnix CC, Herlyn M. The many faces of Notch signaling in skin-derived cells.
Pigment Cell Res. 2007 Dec;20(6):458-65. Review. PubMed [citation] PMID: 17935489
33. Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor
survival. Carcinogenesis. 2013 Jul;34(7):1420-30. doi: 10.1093/carcin/bgt127.
Epub 2013 Apr 12. Review. PubMed [citation] PMID: 23585460, PMCID: PMC3697894
34. Koch U, Radtke F. Notch signaling in solid tumors. Curr Top Dev Biol.
2010;92:411-55. doi: 10.1016/S0070-2153(10)92013-9. Review. PubMed [citation]
PMID: 20816403
35. Kaushik G, Venugopal A, Ramamoorthy P, Standing D, Subramaniam D, Umar S, Jensen
RA, Anant S, Mammen JM. Honokiol inhibits melanoma stem cells by targeting notch
signaling. Mol Carcinog. 2015 Dec;54(12):1710-21. doi: 10.1002/mc.22242. Epub
2014 Dec 9. PubMed [citation] PMID: 25491779, PMCID: PMC4776032
36. Lin X, Sun B, Zhu D, Zhao X, Sun R, Zhang Y, Zhang D, Dong X, Gu Q, Li Y, Liu F.
Notch4+ cancer stem-like cells promote the metastatic and invasive ability of
melanoma. Cancer Sci. 2016 Aug;107(8):1079-91. doi: 10.1111/cas.12978. Epub 2016
Jun 28. PubMed [citation] PMID: 27234159, PMCID: PMC4982579
37. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008
Apr;4(2):68-75. PubMed [citation] PMID: 19279717, PMCID: PMC2634250
38. Kulikova, Ksenia & Kibardin, Alexey & Gnuchev, N.V. & Georgiev, G.P. & Larin, Sergey. (2012). Wnt Signaling Pathway and Its Significance for Melanoma Development. Sovremennye Tehnologii v Medicine. 2012. 107-111.
39. Bachmann IM, Straume O, Puntervoll HE, Kalvenes MB, Akslen LA. Importance of
P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic
tumors and prognosis in cutaneous melanoma. Clin Cancer Res. 2005 Dec 15;11(24 Pt
1):8606-14. PubMed [citation] PMID: 16361544
40. Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major
MB, Hwang ST, Rimm DL, Moon RT. Activated Wnt/beta-catenin signaling in melanoma
is associated with decreased proliferation in patient tumors and a murine
melanoma model. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1193-8. doi:
10.1073/pnas.0811902106. Epub 2009 Jan 14. PubMed [citation] PMID: 19144919,
PMCID: PMC2626610
41. Kovacs D, Migliano E, Muscardin L, Silipo V, Catricalà C, Picardo M, Bellei B.
The role of Wnt/β-catenin signaling pathway in melanoma
epithelial-to-mesenchymal-like switching: evidences from patients-derived cell
lines. Oncotarget. 2016 Jul 12;7(28):43295-43314. doi: 10.18632/oncotarget.9232.
PubMed [citation] PMID: 27175588, PMCID: PMC5190024
42. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev
Cancer. 2013 Apr;13(4):246-57. doi: 10.1038/nrc3458. Epub 2013 Mar 7. Review.
PubMed [citation] PMID: 23467301
43. Nallet-Staub F, Marsaud V, Li L, Gilbert C, Dodier S, Bataille V, Sudol M, Herlyn
M, Mauviel A. Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in
cutaneous melanoma. J Invest Dermatol. 2014 Jan;134(1):123-132. doi:
10.1038/jid.2013.319. Epub 2013 Jul 29. PubMed [citation] PMID: 23897276, PMCID:
PMC3938155
44. Sanchez IM, Aplin AE. Hippo: hungry, hungry for melanoma invasion. J Invest
Dermatol. 2014 Jan;134(1):14-16. doi: 10.1038/jid.2013.372. Erratum in: J Invest
Dermatol. 2014 Jun;134(6):1779. PubMed [citation] PMID: 24352079, PMCID:
PMC3868999
45. O'Reilly KE, de Miera EV, Segura MF, Friedman E, Poliseno L, Han SW, Zhong J,
Zavadil J, Pavlick A, Hernando E, Osman I. Hedgehog pathway blockade inhibits
melanoma cell growth in vitro and in vivo. Pharmaceuticals (Basel). 2013 Nov
11;6(11):1429-50. doi: 10.3390/ph6111429. PubMed [citation] PMID: 24287465,
PMCID: PMC3854019
46. Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V, Beermann F, Ruiz I
Altaba A. Melanomas require HEDGEHOG-GLI signaling regulated by interactions
between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007 Apr
3;104(14):5895-900. Epub 2007 Mar 28. PubMed [citation] PMID: 17392427, PMCID:
PMC1838820
47. Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, Hoek
KS, Juàrez P, Goydos JS, Fournier PJ, Sibon C, Bertolotto C, Verrecchia F, Saule
S, Delmas V, Ballotti R, Larue L, Saiag P, Guise TA, Mauviel A. GLI2-mediated
melanoma invasion and metastasis. J Natl Cancer Inst. 2010 Aug 4;102(15):1148-59.
doi: 10.1093/jnci/djq257. Epub 2010 Jul 21. PubMed [citation] PMID: 20660365,
PMCID:PMC2914763
48. Jalili A, Mertz KD, Romanov J, Wagner C, Kalthoff F, Stuetz A, Pathria G,
Gschaider M, Stingl G, Wagner SN. NVP-LDE225, a potent and selective SMOOTHENED
antagonist reduces melanoma growth in vitro and in vivo. PLoS One. 2013 Jul
30;8(7):e69064. doi: 10.1371/journal.pone.0069064. Print 2013. Erratum in: PLoS
One. 2013;8(9). doi:10.1371/annotation/ddd22094-5d8d-43ef-ad81-b95afe392ec7.
PubMed [citation] PMID: 23935925, PMCID: PMC3728309
Treatment of Metastatic Melanoma. Anticancer Res. 2016 Jul;36(7):3229-41. Review.
PubMed [citation] PMID: 27354579
2. Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, Lok HC,
Sahni S, Lane DJ, Richardson DR. Roads to melanoma: Key pathways and emerging
players in melanoma progression and oncogenic signaling. Biochim Biophys Acta.
2016 Apr;1863(4):770-84. doi: 10.1016/j.bbamcr.2016.01.025. Epub 2016 Feb 1.
Review. PubMed [citation] PMID: 26844774
3. 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, van Baren N, Long GV, Ribas A, Lo RS. Acquired resistance and clonal evolution in melanoma during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93. doi:
10.1158/2159-8290.CD-13-0642. Epub 2013 Nov 21. PubMed [citation] PMID: 24265155,PMCID: PMC3936420
4. Wolchok JD, Chiarion-Sileni V, Gonzalez R, Rutkowski P, Grob JJ, Cowey CL, Lao CD, Wagstaff J, Schadendorf D, Ferrucci PF, Smylie M, Dummer R, Hill A, Hogg D, Haanen J, Carlino MS, Bechter O, Maio M, Marquez-Rodas I, Guidoboni M, McArthur G, Lebbé C, Ascierto PA, Long GV, Cebon J, Sosman J, Postow MA, Callahan MK, Walker D, Rollin L, Bhore R, Hodi FS, Larkin J. Overall Survival with Combined Nivolumab and Ipilimumab in Advanced Melanoma. N Engl J Med. 2017 Oct 5;377(14):1345-1356. doi: 10.1056/NEJMoa1709684. Epub 2017 Sep 11.
5. Fox MC, Lao CD, Schwartz JL, Frohm ML, Bichakjian CK, Johnson TM. Management
options for metastatic melanoma in the era of novel therapies: a primer for the
practicing dermatologist: part I: Management of stage III disease. J Am Acad
Dermatol. 2013 Jan;68(1):1.e1-9; quiz 10-12. doi: 10.1016/j.jaad.2012.09.040.
PubMed [citation] PMID: 23244383
6. Fox MC, Lao CD, Schwartz JL, Frohm ML, Bichakjian CK, Johnson TM. Management
options for metastatic melanoma in the era of novel therapies: a primer for the
practicing dermatologist: part II: Management of stage IV disease. J Am Acad
Dermatol. 2013 Jan;68(1):13.e1-13; quiz 26-8. doi: 10.1016/j.jaad.2012.09.041.
PubMed [citation] PMID: 23244384
7. O'Sullivan Coyne G, Madan RA, Gulley JL. Nivolumab: promising survival signal
coupled with limited toxicity raises expectations. J Clin Oncol. 2014 Apr
1;32(10):986-8. doi: 10.1200/JCO.2013.54.5996. Epub 2014 Mar 3. No abstract
available. PubMed [citation] PMID: 24590655
8. Hodi FS, O'Day SJ, McDermott DF, Weber RW, Sosman JA, Haanen JB, Gonzalez R,
Robert C, Schadendorf D, Hassel JC, Akerley W, van den Eertwegh AJ, Lutzky J,
Lorigan P, Vaubel JM, Linette GP, Hogg D, Ottensmeier CH, Lebbé C, Peschel C,
Quirt I, Clark JI, et al. Improved survival with ipilimumab in patients with
metastatic melanoma. N Engl J Med. 2010 Aug 19;363(8):711-23. doi:
10.1056/NEJMoa1003466. Epub 2010 Jun 5. Erratum in: N Engl J Med. 2010 Sep
23;363(13):1290. PubMed [citation] PMID: 20525992, PMCID: PMC3549297
Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L.
Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol
Res. 2007 Oct;56(4):275-87. Epub 2007 Aug 9. Review. PubMed [citation] PMID:
17897837
9. Weber J. Ipilimumab: controversies in its development, utility and autoimmune
adverse events. Cancer Immunol Immunother. 2009 May;58(5):823-30. doi:
10.1007/s00262-008-0653-8. Epub 2009 Feb 6. Review. PubMed [citation] PMID:
19198837
10. Dolan DE, Gupta S. PD-1 pathway inhibitors: changing the landscape of cancer
immunotherapy. Cancer Control. 2014 Jul;21(3):231-7. Review. PubMed [citation]
PMID: 24955707
11. Johnson DB, Peng C, Sosman JA. Nivolumab in melanoma: latest evidence and
clinical potential. Ther Adv Med Oncol. 2015 Mar;7(2):97-106. doi:
10.1177/1758834014567469. Review. PubMed [citation] PMID: 25755682, PMCID:
PMC4346215
12. Marchesi F, Turriziani M, Tortorelli G, Avvisati G, Torino F, De Vecchis L.
Triazene compounds: mechanism of action and related DNA repair systems. Pharmacol
Res. 2007 Oct;56(4):275-87. Epub 2007 Aug 9. Review. PubMed [citation] PMID:
17897837
13. Garbe C, Eigentler TK, Keilholz U, Hauschild A, Kirkwood JM. Systematic review of
medical treatment in melanoma: current status and future prospects. Oncologist.
2011;16(1):5-24. doi: 10.1634/theoncologist.2010-0190. Epub 2011 Jan 6. Review.
PubMed [citation] PMID: 21212434, PMCID: PMC3228046
14. Atkinson V. Medical management of malignant melanoma. Aust Prescr. 2015
Jun;38(3):74-8. Epub 2015 Mar 11. Review. PubMed [citation] PMID: 26648623,
PMCID: PMC4653963
15. 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, et al. Mutations of
the BRAF gene in human cancer. Nature. 2002 Jun 27;417(6892):949-54. Epub 2002
Jun 9. PubMed [citation] PMID: 12068308
16. 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, et al.
Improved survival with vemurafenib in melanoma with BRAF V600E mutation. N Engl J
Med. 2011 Jun 30;364(26):2507-16. doi: 10.1056/NEJMoa1103782. Epub 2011 Jun 5.
PubMed [citation] PMID: 21639808, PMCID: PMC3549296
17. Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P,
Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C,
Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman
V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre,
open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul
28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25. PubMed
[citation] PMID: 22735384
18. Flaherty KT, Puzanov I, Kim KB, Ribas A, McArthur GA, Sosman JA, O'Dwyer PJ, Lee
RJ, Grippo JF, Nolop K, Chapman PB. Inhibition of mutated, activated BRAF in
metastatic melanoma. N Engl J Med. 2010 Aug 26;363(9):809-19. doi:
10.1056/NEJMoa1002011. PubMed [citation] PMID: 20818844, PMCID: PMC3724529
19. 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, van Baren
N, Long GV, Ribas A, Lo RS. Acquired resistance and clonal evolution in melanoma
during BRAF inhibitor therapy. Cancer Discov. 2014 Jan;4(1):80-93. doi:
10.1158/2159-8290.CD-13-0642. Epub 2013 Nov 21. PubMed [citation] PMID: 24265155,
PMCID: PMC3936420
20. Robert C, Karaszewska B, Schachter J, Rutkowski P, Mackiewicz A, Stroiakovski D,
Lichinitser M, Dummer R, Grange F, Mortier L, Chiarion-Sileni V, Drucis K,
Krajsova I, Hauschild A, Lorigan P, Wolter P, Long GV, Flaherty K, Nathan P,
Ribas A, Martin AM, Sun P, et al. Improved overall survival in melanoma with
combined dabrafenib and trametinib. N Engl J Med. 2015 Jan 1;372(1):30-9. doi:
10.1056/NEJMoa1412690. Epub 2014 Nov 16. PubMed [citation] PMID: 25399551
21. Smalley KS, Fedorenko IV. Inhibition of BRAF and BRAF+MEK drives a metastatic
switch in melanoma. Mol Cell Oncol. 2015 Mar 19;2(4):e1008291. doi:
10.1080/23723556.2015.1008291. eCollection 2015 Oct-Dec. PubMed [citation] PMID:
27308505, PMCID: PMC4905349
22. 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, Millward
M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko
N, Mohr P, et al. Combined BRAF and MEK inhibition versus BRAF inhibition alone
in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. doi:
10.1056/NEJMoa1406037. Epub 2014 Sep 29. PubMed [citation] PMID: 25265492
23. Wehrle-Haller B. The role of Kit-ligand in melanocyte development and epidermal
homeostasis. Pigment Cell Res. 2003 Jun;16(3):287-96. Review. PubMed [citation]
PMID: 12753403
24. Carvajal RD, Antonescu CR, Wolchok JD, Chapman PB, Roman RA, Teitcher J, Panageas
KS, Busam KJ, Chmielowski B, Lutzky J, Pavlick AC, Fusco A, Cane L, Takebe N,
Vemula S, Bouvier N, Bastian BC, Schwartz GK. KIT as a therapeutic target in
metastatic melanoma. JAMA. 2011 Jun 8;305(22):2327-34. doi:
10.1001/jama.2011.746. PubMed [citation] PMID: 21642685, PMCID: PMC3986039
25. Guo J, Si L, Kong Y, Flaherty KT, Xu X, Zhu Y, Corless CL, Li L, Li H, Sheng X,
Cui C, Chi Z, Li S, Han M, Mao L, Lin X, Du N, Zhang X, Li J, Wang B, Qin S.
Phase II, open-label, single-arm trial of imatinib mesylate in patients with
metastatic melanoma harboring c-Kit mutation or amplification. J Clin Oncol. 2011
Jul 20;29(21):2904-9. doi: 10.1200/JCO.2010.33.9275. Epub 2011 Jun 20. PubMed
[citation] PMID: 21690468
26. Atefi M, von Euw E, Attar N, Ng C, Chu C, Guo D, Nazarian R, Chmielowski B,
Glaspy JA, Comin-Anduix B, Mischel PS, Lo RS, Ribas A. Reversing melanoma
cross-resistance to BRAF and MEK inhibitors by co-targeting the AKT/mTOR pathway.
PLoS One. 2011;6(12):e28973. doi: 10.1371/journal.pone.0028973. Epub 2011 Dec 14.
PubMed [citation] PMID: 22194965, PMCID: PMC3237573
27. Penna I, Molla A, Grazia G, Cleris L, Nicolini G, Perrone F, Picciani B, Del
Vecchio M, de Braud F, Mortarini R, Anichini A. Primary cross-resistance to
BRAFV600E-, MEK1/2- and PI3K/mTOR-specific inhibitors in BRAF-mutant melanoma
cells counteracted by dual pathway blockade. Oncotarget. 2016 Jan
26;7(4):3947-65. doi: 10.18632/oncotarget.6600. PubMed [citation] PMID: 26678033,
PMCID: PMC4826182
28. Paluncic J, Kovacevic Z, Jansson PJ, Kalinowski D, Merlot AM, Huang ML, Lok HC,
Sahni S, Lane DJ, Richardson DR. Roads to melanoma: Key pathways and emerging
players in melanoma progression and oncogenic signaling. Biochim Biophys Acta.
2016 Apr;1863(4):770-84. doi: 10.1016/j.bbamcr.2016.01.025. Epub 2016 Feb 1.
Review. PubMed [citation] PMID: 26844774
29. Wu H, Goel V, Haluska FG. PTEN signaling pathways in melanoma. Oncogene. 2003 May
19;22(20):3113-22. Review. PubMed [citation] PMID: 12789288
30. Stahl JM, Cheung M, Sharma A, Trivedi NR, Shanmugam S, Robertson GP. Loss of PTEN
promotes tumor development in malignant melanoma. Cancer Res. 2003 Jun
1;63(11):2881-90. PubMed [citation] PMID: 12782594
31. Dankort D, Curley DP, Cartlidge RA, Nelson B, Karnezis AN, Damsky WE Jr, You MJ,
DePinho RA, McMahon M, Bosenberg M. Braf(V600E) cooperates with Pten loss to
induce metastatic melanoma. Nat Genet. 2009 May;41(5):544-52. doi:
10.1038/ng.356. Epub 2009 Mar 12. PubMed [citation] PMID: 19282848, PMCID:
PMC2705918
32. Pinnix CC, Herlyn M. The many faces of Notch signaling in skin-derived cells.
Pigment Cell Res. 2007 Dec;20(6):458-65. Review. PubMed [citation] PMID: 17935489
33. Capaccione KM, Pine SR. The Notch signaling pathway as a mediator of tumor
survival. Carcinogenesis. 2013 Jul;34(7):1420-30. doi: 10.1093/carcin/bgt127.
Epub 2013 Apr 12. Review. PubMed [citation] PMID: 23585460, PMCID: PMC3697894
34. Koch U, Radtke F. Notch signaling in solid tumors. Curr Top Dev Biol.
2010;92:411-55. doi: 10.1016/S0070-2153(10)92013-9. Review. PubMed [citation]
PMID: 20816403
35. Kaushik G, Venugopal A, Ramamoorthy P, Standing D, Subramaniam D, Umar S, Jensen
RA, Anant S, Mammen JM. Honokiol inhibits melanoma stem cells by targeting notch
signaling. Mol Carcinog. 2015 Dec;54(12):1710-21. doi: 10.1002/mc.22242. Epub
2014 Dec 9. PubMed [citation] PMID: 25491779, PMCID: PMC4776032
36. Lin X, Sun B, Zhu D, Zhao X, Sun R, Zhang Y, Zhang D, Dong X, Gu Q, Li Y, Liu F.
Notch4+ cancer stem-like cells promote the metastatic and invasive ability of
melanoma. Cancer Sci. 2016 Aug;107(8):1079-91. doi: 10.1111/cas.12978. Epub 2016
Jun 28. PubMed [citation] PMID: 27234159, PMCID: PMC4982579
37. Komiya Y, Habas R. Wnt signal transduction pathways. Organogenesis. 2008
Apr;4(2):68-75. PubMed [citation] PMID: 19279717, PMCID: PMC2634250
38. Kulikova, Ksenia & Kibardin, Alexey & Gnuchev, N.V. & Georgiev, G.P. & Larin, Sergey. (2012). Wnt Signaling Pathway and Its Significance for Melanoma Development. Sovremennye Tehnologii v Medicine. 2012. 107-111.
39. Bachmann IM, Straume O, Puntervoll HE, Kalvenes MB, Akslen LA. Importance of
P-cadherin, beta-catenin, and Wnt5a/frizzled for progression of melanocytic
tumors and prognosis in cutaneous melanoma. Clin Cancer Res. 2005 Dec 15;11(24 Pt
1):8606-14. PubMed [citation] PMID: 16361544
40. Chien AJ, Moore EC, Lonsdorf AS, Kulikauskas RM, Rothberg BG, Berger AJ, Major
MB, Hwang ST, Rimm DL, Moon RT. Activated Wnt/beta-catenin signaling in melanoma
is associated with decreased proliferation in patient tumors and a murine
melanoma model. Proc Natl Acad Sci U S A. 2009 Jan 27;106(4):1193-8. doi:
10.1073/pnas.0811902106. Epub 2009 Jan 14. PubMed [citation] PMID: 19144919,
PMCID: PMC2626610
41. Kovacs D, Migliano E, Muscardin L, Silipo V, Catricalà C, Picardo M, Bellei B.
The role of Wnt/β-catenin signaling pathway in melanoma
epithelial-to-mesenchymal-like switching: evidences from patients-derived cell
lines. Oncotarget. 2016 Jul 12;7(28):43295-43314. doi: 10.18632/oncotarget.9232.
PubMed [citation] PMID: 27175588, PMCID: PMC5190024
42. Harvey KF, Zhang X, Thomas DM. The Hippo pathway and human cancer. Nat Rev
Cancer. 2013 Apr;13(4):246-57. doi: 10.1038/nrc3458. Epub 2013 Mar 7. Review.
PubMed [citation] PMID: 23467301
43. Nallet-Staub F, Marsaud V, Li L, Gilbert C, Dodier S, Bataille V, Sudol M, Herlyn
M, Mauviel A. Pro-invasive activity of the Hippo pathway effectors YAP and TAZ in
cutaneous melanoma. J Invest Dermatol. 2014 Jan;134(1):123-132. doi:
10.1038/jid.2013.319. Epub 2013 Jul 29. PubMed [citation] PMID: 23897276, PMCID:
PMC3938155
44. Sanchez IM, Aplin AE. Hippo: hungry, hungry for melanoma invasion. J Invest
Dermatol. 2014 Jan;134(1):14-16. doi: 10.1038/jid.2013.372. Erratum in: J Invest
Dermatol. 2014 Jun;134(6):1779. PubMed [citation] PMID: 24352079, PMCID:
PMC3868999
45. O'Reilly KE, de Miera EV, Segura MF, Friedman E, Poliseno L, Han SW, Zhong J,
Zavadil J, Pavlick A, Hernando E, Osman I. Hedgehog pathway blockade inhibits
melanoma cell growth in vitro and in vivo. Pharmaceuticals (Basel). 2013 Nov
11;6(11):1429-50. doi: 10.3390/ph6111429. PubMed [citation] PMID: 24287465,
PMCID: PMC3854019
46. Stecca B, Mas C, Clement V, Zbinden M, Correa R, Piguet V, Beermann F, Ruiz I
Altaba A. Melanomas require HEDGEHOG-GLI signaling regulated by interactions
between GLI1 and the RAS-MEK/AKT pathways. Proc Natl Acad Sci U S A. 2007 Apr
3;104(14):5895-900. Epub 2007 Mar 28. PubMed [citation] PMID: 17392427, PMCID:
PMC1838820
47. Alexaki VI, Javelaud D, Van Kempen LC, Mohammad KS, Dennler S, Luciani F, Hoek
KS, Juàrez P, Goydos JS, Fournier PJ, Sibon C, Bertolotto C, Verrecchia F, Saule
S, Delmas V, Ballotti R, Larue L, Saiag P, Guise TA, Mauviel A. GLI2-mediated
melanoma invasion and metastasis. J Natl Cancer Inst. 2010 Aug 4;102(15):1148-59.
doi: 10.1093/jnci/djq257. Epub 2010 Jul 21. PubMed [citation] PMID: 20660365,
PMCID:PMC2914763
48. Jalili A, Mertz KD, Romanov J, Wagner C, Kalthoff F, Stuetz A, Pathria G,
Gschaider M, Stingl G, Wagner SN. NVP-LDE225, a potent and selective SMOOTHENED
antagonist reduces melanoma growth in vitro and in vivo. PLoS One. 2013 Jul
30;8(7):e69064. doi: 10.1371/journal.pone.0069064. Print 2013. Erratum in: PLoS
One. 2013;8(9). doi:10.1371/annotation/ddd22094-5d8d-43ef-ad81-b95afe392ec7.
PubMed [citation] PMID: 23935925, PMCID: PMC3728309
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Jul 6, 2018
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Chow, P., Angulo, P., & Adkins, K. K. (2018). Current Therapy for Advanced Melanoma and a Look at Future Signaling Pathways to Target. SKIN The Journal of Cutaneous Medicine, 2(4), 224–235. https://doi.org/10.25251/skin.2.4.4
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