Abstract
BackgroundDrug resistance remains an unsolved clinical issue in oncology. Despite promising initial responses obtained with BRAF and MEK kinase inhibitors, resistance to treatment develops within months in virtually all melanoma patients.MethodsMicroarray analyses were performed in BRAF inhibitor-sensitive and resistant cell lines to identify changes in the transcriptome that might play a role in resistance. siRNA approaches and kinase inhibitors were used to assess the involvement of the identified Anaplastic Lymphoma Kinase (ALK) in drug resistance. The capability of extracellular vesicles (EVs) to transfer drug resistant properties was investigated in co-culture assays.ResultsHere, we report a new mechanism of acquired drug resistance involving the activation of a novel truncated form of ALK. Knock down or inhibition of ALK re-sensitised resistant cells to BRAF inhibition and induced apoptosis. Interestingly, truncated ALK was also secreted into EVs and we show that EVs were the vehicle for transferring drug resistance.ConclusionsTo our knowledge, this is the first report demonstrating the functional involvement of EVs in melanoma drug resistance by transporting a truncated but functional form of ALK, able to activate the MAPK signalling pathway in target cells. Combined inhibition of ALK and BRAF dramatically reduced tumour growth in vivo. These findings make ALK a promising clinical target in melanoma patients.
Highlights
Drug resistance remains an unsolved clinical issue in oncology
We show for the first time that the overexpressed ALKRES is secreted into extracellular vesicles (EVs) and is transferred to sensitive, Anaplastic Lymphoma Kinase (ALK)-negative melanoma cells
Characterisation of vemurafenib-sensitive and -resistant A375 melanoma cells BRAFV600E A375 cells were made resistant to 1 μM PLX4032 over a period of eight weeks with constant exposure to the drug
Summary
Drug resistance remains an unsolved clinical issue in oncology. Despite promising initial responses obtained with BRAF and MEK kinase inhibitors, resistance to treatment develops within months in virtually all melanoma patients. Compared to other solid cancers, this most aggressive form of skin cancer exhibits an extremely high prevalence of somatic mutations [1, 2], which is almost entirely attributable to UV light exposure. Despite this high genetic heterogeneity, 40–60% of melanoma patients carry mutations in the Ser/Thr-kinase BRAF (most often V600E), which renders the BRAF kinase and the downstream MAPK signalling pathway constitutively active [3]. ALK can be activated by translocations or mutations making it an oncogene in a variety of malignancies, such as non-small cell lung cancer, anaplastic large cell lymphoma, neuroblastoma and many more [13]. In 2015, Wiesner and colleagues identified in 11% of melanoma tissues a truncated ALK transcript starting from intron 19 and resulting in a smaller protein, which was shown to be oncogenic [14]
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