MAP kinase pathway gene copy alterations in NRAS/BRAF wild‐type advanced melanoma

Recent therapeutic advances have improved melanoma patientś clinical outcome. Novel therapeutics targeting BRAF, NRAS and cKit mutant melanomas are widely used in clinical practice. However therapeutic options in NRASwild‐type/BRAFwild‐type/cKitwild‐type melanoma patients are limited. Our study show...

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Veröffentlicht in:International journal of cancer 2016-05, Vol.138 (9), p.2257-2262
Hauptverfasser: Orouji, Elias, Orouji, Azadeh, Gaiser, Timo, Larribère, Lionel, Gebhardt, Christoffer, Utikal, Jochen
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Sprache:eng
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Zusammenfassung:Recent therapeutic advances have improved melanoma patientś clinical outcome. Novel therapeutics targeting BRAF, NRAS and cKit mutant melanomas are widely used in clinical practice. However therapeutic options in NRASwild‐type/BRAFwild‐type/cKitwild‐type melanoma patients are limited. Our study shows that gene copy numbers of members of the MAPK signaling pathway vary in different melanoma subgroups. NRASwild‐type/BRAFwild‐type melanoma metastases are characterized by significant gains of MAP2K1 (MEK1) and MAPK3 (ERK1) gene loci. These additional gene copies could lead to an activation of the MAPK signaling pathway via a gene‐dosage effect. Our results suggest that downstream analyses of the pMEK and pERK expression status in NRASwild‐type/BRAFwild‐type melanoma patients identify patients that could benefit from targeted therapies with MEK and ERK inhibitors. What's new? Although several therapeutic options have recently become available for BRAF/NRAS‐mutant melanomas, a gap remains for BRAF/NRAS wild‐type disease, which accounts for about 10‐30 percent of melanoma cases. A major reason for the disparity is a lack of therapeutic targets for wild‐type tumors. This study shows that NRAS/BRAF wild‐type melanomas have significant increases in MAP2K1 (MEK1) and MAPK3 (ERK1) gene copy number, setting the stage for the activation of MAPK signaling. The findings suggest that MAPK activation is a significant feature of NRAS/BRAF wild‐type melanomas, possibly rendering this subset of melanomas sensitive to MEK/ERK targeted therapies.
ISSN:0020-7136
1097-0215
DOI:10.1002/ijc.29970