The mechanisms involved in the development of vemurafenib resistance in human melanoma cells

    Item Description
    Linked Agent
    Thesis advisor: Hess, Angela
    Committee member: Beishline, Kate
    Committee member: Brubaker, Kristen
    Degree granting institution: Bloomsburg University of Pennsylvania
    Degree name: Master of Science
    Date Created
    2022
    Note

    Cutaneous melanoma may not be the most common skin cancer; however, it is the deadliest. For patients with metastatic melanoma the survival rates drop to 15%. Vemurafenib inhibits a specific mutation in B-Raf (V600E) found in metastatic melanomas. Although vemurafenib is somewhat effective in treating melanoma, resistance to the drug occurs at a frequent rate. Resistance to vemurafenib has recently been associated with increased EphA2 expression. EphA2 expression is associated with aggressive forms of melanoma and increased melanoma plasticity as characterized by vasculogenic mimicry (VM). This study explored the mechanisms involved in the development of resistance to vemurafenib by investigating changes in EphA2 expression and vasculogenic mimicry in resistant and non-resistant cells. The data collected demonstrates that the A375P vemurafenib resistant (VR) cells had an increase in proliferation and migration when compared with the non-resistant cells. A375P VR cells also had an increase in expression of phosphorylated Erk1/2, Erk1/2, and EphA2, compared to that of the non-resistant A375P cells. However, the EphA2 expression at the mRNA level for both the resistant and non-resistant cell lines were comparable, therefore, it was predicted that the increase in EphA2 protein expression was due to post-translational modifications. Experiments to test increased plasticity of vemurafenib resistant cells demonstrated A375P VR cells have adapted the ability to engage in VM. This study sheds light on the mechanisms associated with vemurafenib resistance and provide insight into the development of new therapeutic approaches for the treatment of melanoma.

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