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Review
. 2024 Oct 26;25(21):11502.
doi: 10.3390/ijms252111502.

Amelanotic Melanoma-Biochemical and Molecular Induction Pathways

Piotr Misiąg  1   2 , Klaudia Molik  1   2 , Monika Kisielewska  1   2 , Paulina Typek  1   2 , Izabela Skowron  1   2 , Anna Karwowska  1   2 , Jacek Kuźnicki  1   2 , Aleksandra Wojno  1   2 , Marcin Ekiert  3 , Anna Choromańska  4
Affiliations
Review

Amelanotic Melanoma-Biochemical and Molecular Induction Pathways

Piotr Misiąg et al. Int J Mol Sci. .

Abstract

Amelanotic melanoma (AM) is a subtype of hypomelanotic or completely amelanotic melanoma. AM is a rare subtype of melanoma that exhibits a higher recurrence rate and aggressiveness as well as worse surveillance than typical melanoma. AM shows a dysregulation of melanin production, cell cycle control, and apoptosis pathways. Knowing these pathways has an application in medicine due to targeted therapies based on the inhibiting elements of the abovementioned pathways. Therefore, we summarized and discussed AM biochemical and molecular induction pathways and personalized medicine approaches, clinical management, and future directions due to the fact that AM is relatively rare. AM is commonly misdiagnosed. Hence, the role of biomarkers is becoming significant. Nonetheless, there is a shortage of biomarkers specific to AM. BRAF, NRAS, and c-KIT genes are the main targets of therapy. However, the role of BRAF and KIT in AM varied among studies. BRAF inhibitors combined with MAK inhibitors demonstrate better results. Immune checkpoint inhibitors targeting CTLA-4 combined with a programmed death receptor 1 (PD-1) show better outcomes than separately. Fecal microbiota transplantation may overcome resistance to immune checkpoint therapy of AM. Immune-modulatory vaccines against indoleamine 2,3-dioxygenase (IDO) and PD ligand (PD-L1) combined with nivolumab may be efficient in melanoma treatment.

Keywords: amelanotic melanoma; biomarkers; immunotherapy; melanogenesis; melanoma; precision medicine; prognostic factors; targeted therapy.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
The schema of the melanogenesis pathway. Tyrosinase is an enzyme that catalyzes the conversion of L-tyrosine into L-DOPA. Tyrosinase-related protein 1 (TRP-1) and tyrosinase-related protein 2 (TRP-2) stabilize and increase the activity of TYR. Moreover, TRP-1 upturns the eumelanin vs. pheomelanin ratio. TRP-2 takes part in the tautomerization of DOPA chrome into DHI-2-carboxylic acid (DHICA). TRP-1 oxidases DHICA. The figure is based on the data of the studies [27,28,29].
Figure 2
Figure 2
The role of the PI3K/AKT pathway in AM. RTK and RAS induce PI3K, which triggers PIP2 to PIP3 transition. PIP3 activates through AKT mTOR, Bad, and MdM2. These factors cause cell growth and survival.
Figure 3
Figure 3
The role of Tregs in immune system suppression in AM.
See this image and copyright information in PMC

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