A new ALK isoform transported by extracellular vesicles confers drug resistance to melanoma cells

Giulia Cesi, Demetra Philippidou, Ines Kozar, Yeoun Jin Kim, Francois Bernardin, Guillaume Van Niel, Anke Wienecke-Baldacchino, Paul Felten, Elisabeth Letellier, Sonja Dengler, Dorothee Nashan, Claude Haan, Stephanie Kreis*

*Corresponding author for this work

    Research output: Contribution to journalArticleResearchpeer-review

    55 Citations (Scopus)

    Abstract

    Background: 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. Methods: Microarray 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. Results: Here, 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. Conclusions: To 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.

    Original languageEnglish
    Article number145
    JournalMolecular Cancer
    Volume17
    Issue number1
    DOIs
    Publication statusPublished - 5 Oct 2018

    Keywords

    • ALK
    • Drug resistance
    • Extracellular vesicles
    • Kinase inhibitors
    • Melanoma

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