Resistance to c-Kit inhibitors in melanoma

Insights for future therapies

Matteo S. Carlino, Jason R. Todd, Helen Rizos*

*Corresponding author for this work

    Research output: Contribution to journalArticle

    13 Citations (Scopus)
    11 Downloads (Pure)

    Abstract

    Mutations activating the receptor tyrosine kinase c-Kit occur commonly in melanomas arising on mucosal membranes and acral skin. Clinical studies have demonstrated that selective inhibition of c-Kit is effective in treating patients with c-Kit mutant gastrointestinal stromal tumors, but c-Kit inhibitor activity has been disappointing in c-Kit mutant melanoma patients. Activated c-Kit utilises phosphatidylinositol 3-kinase (PI3K) signalling as the dominant effector of cell proliferation and survival with the mitogen-activated protein kinase (MAPK) cascade serving as an ancillary survival pathway. We confirmed that these pathways are reactivated in melanoma cells with acquired resistance to c-Kit inhibitors and that these resistant sublines remain sensitive to the concurrent inhibition of MAPK and PI3K signalling. These findings suggest that durable responses in c-Kit mutant melanoma may require combination therapies that selectively inhibit critical downstream proliferative and survival pathways. We also discuss the interaction between targeted therapies and anti-tumor immune responses and the need to consider immunotherapies in new combinatorial treatment approaches.

    Original languageEnglish
    Pages (from-to)423-426
    Number of pages4
    JournalOncoscience
    Volume1
    Issue number6
    DOIs
    Publication statusPublished - 2014

    Bibliographical note

    Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

    Keywords

    • C-Kit
    • MAPK
    • PI3K

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