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The role of SOX2 in resistance towards targeted therapy

Hüser, Laura

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Abstract

Melanoma is often characterized by a constitutively active MAP kinase pathway. For inhibition of the aberrantly activated MAP kinase pathway targeted therapies with specific BRAF inhibitors are available that are very effective in the beginning but futile as soon as resistance occurs after a few months. Hence, a better understanding of the mechanisms mediating resistance is necessary to increase the success of the treatment. In this study I observed that SOX2 and CD24 were upregulated shortly after the BRAF inhibitor treatment was started. A similar upregulation was seen in melanoma-derived induced pluripotent cancer cells (iPCCs) which are resistant to targeted therapy. SOX2 and CD24 are known to promote an undifferentiated and cancer stem cell-like phenotype associated with resistance. Therefore, I elucidated the role of SOX2 and CD24 in resistance to targeted therapy in more detail. I found that the upregulation of SOX2 and CD24 required activation of STAT3. The STAT3 activation was caused by soluble factors which were at least partially cleaved by sheddases. Moreover, I detected that SOX2 induced the expression of CD24 by binding to its promoter. Additionally, I found that the overexpression of SOX2 significantly increased the resistance towards BRAF inhibitors, while SOX2 knockdown rendered the cells more sensitivity towards treatment. CD24 overexpression could mimic the effect of SOX2 overexpression while CD24 knockdown in SOX2 overexpressing cells re-established the sensitivity towards BRAF inhibitors. Furthermore, the overexpression of CD24 or SOX2 induced Src and STAT3 activity. Importantly, the more resistant SOX2 or CD24 overexpressing cells were still sensitive to Src/STAT3 inhibition. In contrast, in acquired resistance neither SOX2 nor CD24 played a major role. Here, other molecules and pathways mediate the cells’ resistance to the treatment. Therefore, I suggest that the BRAF inhibitor induced activation of STAT3 and the resulting increased expression of SOX2 and CD24 work as an escape pathway to save some cancer cells from the BRAF inhibitor-induced cell death. In the long term these cells can then acquire other mechanisms to circumvent the BRAF inhibitor action and regrow. Thus, to prevent adaptive resistance it might be beneficial to combine Src/STAT3 inhibitors together with MAP kinase pathway inhibitors.

Item Type: Dissertation
Supervisor: Umansky, Prof. Dr. Viktor
Date of thesis defense: 8 June 2018
Date Deposited: 03 Jul 2018 07:10
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 570 Life sciences
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