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Review
. 2013 Sep-Nov;28(5-6):267-74.
doi: 10.3109/08820538.2013.825278.

The role of genetics in the pathogenesis of periocular cutaneous neoplasms: implications for targeted therapy

Nahyoung Grace Lee  1 , Leo A Kim, Suzanne K Freitag
Affiliations
Review

The role of genetics in the pathogenesis of periocular cutaneous neoplasms: implications for targeted therapy

Nahyoung Grace Lee et al. Semin Ophthalmol. 2013 Sep-Nov.

Abstract

In the past, cutaneous malignancies of the periocular region were primarily treated surgically with few other options. As the genetic bases of these tumors have become elucidated, targeted therapies aimed specifically at pathways that are felt to be responsible for cellular proliferation and uncontrolled growth have emerged with new promise. This review contains a summary of the various genetic implications of cutaneous neoplasms as well as their corresponding targeted systemic therapies.

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Conflict of interest statement

None of the authors have any financial interests or disclosures.

Figures

Figure 1
Figure 1
Sonic hedgehog pathway. In the absence of ligand, the Sonic hedgehog (Shh) receptor, patched (PTCH) inhibits signaling through inhibition of the transmembrane protein Smoothened (SMO). Ligand occupation of PTCH inactivates the receptor and allows activation of SMO that, in turn, results in the induction of GLI transcription factors. Vismodegib, cyclopamine, and itraconazole are inhibitors of SMO whereas arsenic trioxide acts by inhibiting GLI.
Figure 2
Figure 2
Epidermal growth factor receptor (EGFR) pathway. EGFR is a receptor tyrosine kinase that, when bound to growth factor, causes downstream activation and phosphorylation of the protein kinase cascade and eventual transcription of EGFR target genes. Cetuximab, erlotinib, and gefitinib are examples of EGFR inhibitors that act specifically by inhibiting the receptor tyrosine kinase.
Figure 3
Figure 3
Pathways in melanomagenesis. The receptor tyrosine kinase, when bound to a growth factor activates the ERK/MAP kinase pathway. The G-protein coupled receptor MC1R (melanocortin 1 receptor), when occupied by ligand melanocortin (MC) activates BRAF through cAMP. Oncogenic BRAF constitutively activates MEK and this results in a strong and sustained activation of ERK. The gene CDKN2A encodes p16, which inhibits cyclin-dependent kinase 4 (CDK4). CDK4, when activated, leads to phosphorylation of the Retinoblastoma protein (Rb) and subsequent cell-cycle progression. Loss of CDKN2A, therefore, leads to tumorigenesis through this pathway. So far, medications have been developed to inhibit the receptor tyrosine kinase itself as well as BRAF and MEK, directly.
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