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UBC Theses and Dissertations

Investigating MYC and IL-6/JAK/STAT3 signaling in treatment resistance of Group 3 medulloblastoma Kaprelova, Natasha

Abstract

Medulloblastoma (MB) is the most common malignant pediatric brain tumour, with the Group 3 subtype having the worst prognosis due to amplification of the Myc proto-oncogene. The IL-6/JAK/STAT3 pathway renders tumour cells chemoresistant via an autocrine feedback loop that sustains high STAT3 levels. STAT3 is activated by IL-6 cytokine stimulation and induces the expression of target genes, including Myc, that promote uncontrolled proliferation, survival, metastasis, and chemoresistance of tumour cells. However, very little is known about the exact mechanism(s) amplification and overexpression of Myc contribute to the development and aggressive nature of Group 3 medulloblastomas. Here, I evaluated whether IL-6 cytokine-mediated constitutive activation of STAT3 mediates Myc overexpression in these tumors. IL-6 cytokines transiently increased Myc expression in Group 3 MB cells. Furthermore, abrogation of STAT3 expression led to an IL-6-mediated increase in Myc expression, suggesting that another pathway may be a key regulator of Myc overexpression in Group 3 MB tumours. Additionally, I demonstrated that both gp130-/- and STAT3-/- cells showed increased sensitivity to vincristine compared with wild-type Med8A cells, which was not correlated to changes in Myc levels between the 3 cell lines. While this finding aligns with our conventional understanding of STAT3’s role in drug resistance, it also suggests that high Myc expression alone may not be sufficient to confer chemoresistance in Group 3 MB cells. I postulated that well-known Myc inhibitors, 10058-F4 and 10074-G5, can be effective in reducing Group 3 tumour cell proliferation. Both 10058-F4 and 10074-G5 inhibitors effectively reduced Med8A cell proliferation in a dose-dependent manner, with 10074-G5 demonstrating higher potency. Additionally, I demonstrated that lower concentrations of 10058-F4 and 10074-G5 inhibitors were sufficient to reduce Myc protein levels despite the fact that high doses were required for significant growth inhibition. My findings suggest that the partial inhibition of Myc may not be sufficient to impair cellular proliferation. Overall, understanding the interplay between the IL-6/JAK/STAT3 pathway and Myc overexpression in Group 3 MB could inform the development of targeted therapies, and evaluating the efficacy of Myc inhibitors in this context may open new avenues for the treatment of aggressive pediatric brain cancers.

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Attribution-NonCommercial-NoDerivatives 4.0 International