The current development of BRAF inhibitors has revolutionized the treatment of unresectable melanoma.,As the potential heterogeneity of BRAF mutations in melanoma has been reported, accurate detection of BRAF mutations are important.,However, the genetic heterogeneity of acral melanoma-a distinct type of melanoma with a unique genetic background-has not fully been investigated.,We conducted a retrospective review of our acral melanoma patients.,Of the 196 patients with acral melanoma, we retrieved 31 pairs of primary and matched metastatic melanomas.,We immunostained the 31 pairs with VE1, a BRAFV600E-mutation-specific monoclonal antibody.,Immunohistochemistry with VE1 showed a high degree of sensitivity and specificity for detecting BRAFV600E mutations compared with the real-time polymerase chain reaction method.,A total of nine primary (29.0%) and eight metastatic (25.8%) acral melanomas were positive for VE1.,In three patients (9.7%), we observed a discordance of VE1 staining between the primary and metastatic lesions.,Of note, VE1 immunohistochemical staining revealed a remarkable degree of intra-tumor genetic heterogeneity in acral melanoma.,Our study reveals that VE1 immunostaining is a useful ancillary method for detecting BRAFV600E mutations in acral melanoma and allows for a clear visualization of intra- and inter-tumor BRAF heterogeneity.
Melanoma is a molecularly heterogeneous disease with many genetic mutations and altered signaling pathways.,Activating mutations in the BRAF oncogene are observed in approximately 50% of cutaneous melanomas and the use of BRAF inhibitor (BRAFi) compounds has been reported to improve the outcome of patients with BRAF-mutated metastatic melanoma.,However, the majority of these patients develop resistance within 6-8 months following the initiation of BRAFi treatment.,In this study, we examined the possible use of the poly(ADP-ribose) polymerase 1 (PARP1) inhibitor, ABT-888 (veliparib), as a novel molecule that may be successfully employed in the treatment of BRAFi-resistant melanoma cells.,Sensitive and resistant to BRAFi dabrafenib A375 cells were exposed to increasing concentrations of ABT-888.,Cell viability and apoptosis were assessed by MTT assay and Annexin V-FITC analysis, respectively.,The cell migratory and invasive ability was investigated using the xCELLigence technology and Boyden chamber assays, respectively.,ABT-888 was found to reduce cell viability and exhibited pro-apoptotic activity in melanoma cell lines, independently from the BRAF/NRAS mutation status, in a dose-dependent manner, with the maximal effect being reached in the 25-50 µM concentration range.,Moreover, ABT-888 promoted apoptosis in both the sensitive and resistant A375 cells, suggesting that ABT-888 may be useful in the treatment of BRAFi-resistant subsets of melanoma cells.,Finally, in accordance with the involvement of PARP1 in actin cytoskeletal machinery, we found that the cytoskeletal organization, motility and invasive capability of both the A375 and A375R cells decreased upon exposure to 5 µM ABT-888 for 24 h.,On the whole, the findings of this study highlight the pivotal role of PARP1 in the migration and invasion of melanoma cells, suggesting that ABT-888 may indeed be effective, not only as a pro-apoptotic drug for use in the treatment of BRAFi-resistant melanoma cells, but also in suppressing their migratory and invasive activities.