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Molecular Mechanisms of Melanoma Resident CoRneR Molecular Mechanisms of Melanoma Amanda Pickert, MD here has been a rapid accumulation of knowl- on other proteins to amplify the signal or enter- edge regarding the altered molecular path- ing the nucleus and altering gene transcription. Tways in melanoma. With the development Mutations enhancing kinase activity or disrupting of targeted therapies such as vemurafenib and other their intracellular regulation allow for inappropriate therapies in clinical trials, melanomas may eventu- cell survival and growth. Usually cancer progression ally be classified based on their altered molecular requires the deregulation of multiple important pro- mechanisms. Knowledge of these emerging molecular liferation and survival pathways. melanoma subtypes is not only testable on boards but Described genetic alterations include amplifica- also is important for potentially understanding the tions, deletions, and mutations in kinases, their future direction of melanoma therapy. What are your regulators, and receptors. For melanoma, the im- thoughts on targeted therapies? DespiteCUTIS high expec- portant oncogenes are neuroblastoma retrovirus- tations, vemurafenib for many patients only prolongs associated DNA sequence (N-ras) viral oncogene survival by months with high rates of melanoma homolog, v-raf murine sarcoma viral oncogene resistance developing thereafter. Thus far vemu- homolog B1 (BRAF), Akt protein kinase, c-kit re- rafenib has not been a miracle drug but represents a ceptor, guanine nucleotide binding protein alpha new approach to cancersDo that may offer Not future cures. q polypeptideCopy (Gnaq), and guanine nucleotide bind- Herein I will review the presently known altered ing protein (G protein) alpha 11 (Gna11) (Figure). molecular pathways in melanoma, focusing on infor- Any oncogene that undergoes a mutation causing mation that may be tested on board examinations. it to gain function contributes to cancer evolution. I do advise though that cancer biology is incred- Important tumor suppressor genes are cyclin- ibly complex with substantial overlap and cross-talk dependent kinase inhibitor 2A (CDKN2A), phos- between the numerous signaling pathways, which phatase and tensin homolog (PTEN), and a 53-kd makes any discussion a challenge. protein. Tumor suppressor genes serve as regulators The deregulation of kinases is one of the prin- by curbing cell survival and proliferation, especially ciple mechanisms by which cancer develops.1 After after a cellular insult resulting in DNA damage. a cell surface receptor binds its ligand, a signal trans- Alterations in tumor suppressor genes are usually duction pathway is activated to communicate the defined by a loss of function. Therapeutically, the information to the nucleus where gene transcrip- inhibition of an oncogene is more feasible, such as tion is altered and an appropriate response to the targeting an overexpressed oncogenic protein, than signal is generated such as cell survival and growth. replacing a deleted tumor suppressor gene. Signal propagation occurs by the kinase-dependent phosphorylation of proteins. Kinases perform this Oncogenes activity by transferring a phosphate from adenosine Activated N-ras, a membrane-bound small G pro- triphosphate to the hydroxyl group of serine, threo- tein, activates BRAF. N-ras becomes active when an nine, or tyrosine.1 Once phosphorylated, targeted appropriate receptor (usually a growth factor recep- proteins propagate the cascade by either turning tor) binds its ligand, causing it to switch guanosine diphosphate for guanosine triphosphate. BRAF as well as many other downstream mediators are serine/ From Mayo Clinic Arizona, Scottsdale. threonine protein kinases. This signaling cascade The author reports no conflict of interest. is known as the MAPK (mitogen-activated protein WWW.CUTIS.COM VOLUME 89, MARCH 2012 E1 Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Resident Corner CUTIS Do Not Copy Melanomagenesis. FLT3 indicates FMS-like tyrosine kinase 3; PDGF, platelet-derived growth factor; GF, growth factor; VEGF, vascular endothelial growth factor; N-ras, neuroblastoma retrovirus-associated DNA sequence; PI3K, phosphatidylinositol 3-kinases; PTEN, phosphatase and tensin homolog; BRAF, v-raf murine sarcoma viral oncogene homolog B1; MTOR, mechanistic target of rapamycin; MEK, mitogen-activated protein kinase; ERK, extracellular signal-regulated kinases; Gnaq, guanine nucleotide binding protein alpha q polypeptide; Gna11, guanine nucleotide binding protein (G protein) alpha 11; BCL2, b-cell lymphoma 2; BAD, BCL2-associated agonist of cell death; CREB, cAMP response element binding; MITF, microphthalmia-associated transcription factor. kinases)/ERK (extracellular signal-regulated kinases) characterized by heart defects, mental retardation, pathway. The end result of the cascade is altered cutaneous abnormalities (ie, xerosis, ichthyosis, kera- DNA transcription leading to cell cycle progression tosis pilaris), and a distinctive facial appearance.4 and survival. In 15% to 20% of melanomas, N-ras is Other cancers associated with BRAF mutations mutated. N-ras, when turned on, also activates the include non-Hodgkin lymphoma, colorectal cancer, phosphatidylinositol 3-kinases (PI3K)/AKT path- papillary thyroid carcinoma, and non-small cell lung way.2 Harvey rat sarcoma (H-ras), another member carcinoma. Benign nevi are well-known to have BRAF of the ras family, mutations are found in spitz nevi. mutations, and the presence of a BRAF mutation alone Up to 60% of melanomas on nonchronically sun- is usually insufficient for malignant transformation. damaged skin (intermittent sun exposure) contain BRAF mutations usually work in concert with others, acquired mutations in BRAF.3 Inherited mutations in which explains why BRAF-positive melanomas may BRAF cause cardiofaciocutaneous syndrome, a disease overcome the BRAF inhibitor vemurafenib. More E2 CUTIS® WWW.CUTIS.COM Copyright Cutis 2012. No part of this publication may be reproduced, stored, or transmitted without the prior written permission of the Publisher. Resident Corner than 95% of the mutations affecting BRAF switch degradation of p53. (p53 Will be discussed below.) a valine residue at the 600 amino acid for a glu- Similarly, p16 binds to cyclin-dependent kinases tamic acid, resulting in constitutive activation of 4 and 6 (CDK4/CDK6), preventing their interac- the kinase.5 tion with cyclin D. Cyclin D when bound to CDK4/ The PI3K/AKT signal transduction cascade, simi- CDK6 advances both the G1 and S phase of cell cycle. lar to most pathways, can be activated by more The S phase of cell cycle is advanced by the cyclin D than one mechanism including N-ras.5 The crucial CDK4/CDK6 complex, triggering the phosphorylation downstream mediator of this pathway is the Akt of retinoblastoma protein, leading to its degradation. kinase, which has many functions but most notably Retinoblastoma protein, when present, inhibits the stimulates the transcription of proteins preventing S phase of cell cycle by binding unphosphorylated E2F apoptosis. It also inhibits BCL2-associated agonist in the nucleus. E2F, when unbound, initiates the S phase of cell death (BAD), a proapoptotic protein, and of cell cycle. The CDKN2A gene is a key susceptibil- activates mechanistic target of rapamycin (MTOR), ity locus for familial melanoma and may also be an a serine/threonine protein kinase that has its own sig- acquired mutation present in nonfamilial melanomas.5 naling cascade promoting cell growth and prolifera- The name p53 comes from its molecular mass; tion. The downstream phosphorylation of Akt kinase its presence can arrest both the G1 and S phase of is tightly regulated by PTEN. PTEN is a phosphatase cell cycle. p53 Is crucial in halting cellular division that switches off PI3K/AKT transmission by remov- after acquirement of DNA damage. If the damage is ing a phosphate from a key protein, thus reverting the irreparable, p53 initiates apoptosis by directing the signal transduction pathway to the off position after transcription and activation of proapoptotic genes. activation. Akt kinase deregulation occurs in more p53 Is mutated in more than half of all human than 60% of melanomas, often in conjunction with cancers and in approximately 10% of melanomas.5,8 BRAF mutations. V-akt murine thymoma viral onco- Usually patients with p53 mutations are less respon- gene homolog 1 (AKT1) mutations have been found sive to chemotherapy because most chemotherapy to cause Proteus syndrome, not PTEN mutations as drugs depend on apoptosis initiation pathways to previously thought.5 CUTIShave their effect. 5 Li-Fraumeni syndrome is a rare, c-kit Receptor mutations are found in 20% to autosomal, dominantly inherited mutation in the 40% of melanomas on acral, mucosal, and chronically p53 gene. Affected individuals have dramatically sun-damaged skin.6 c-kit Is a receptor tyrosine kinase increased susceptibility to cancers including the that regulates the intracellular processes of growth, breast, brain, leukemia, and sarcomas. division, and migrationDo in response to theNot binding of PTENCopy protein is a phosphatase that negatively its ligand stem cell factor, also known as steel factor.5 regulates the PI3K/AKT signal transduction path- c-kit Signal transduction is at least partly mediated way. It dephosphorylates the signaling molecule through the MAPK/ERK pathway.7 Therefore, muta- phosphatidylinositol 3,4,5-triphosphate,
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