SOX-2 mediated upregulation of CD24 promotes adaptive resistance towards targeted therapy in melanoma

ABSTRACT: Melanoma is one of the most aggressive types of skin cancer and is often characterized by a constitutively activate RAS-RAF-MEK-ERK pathway. For targeted therapy, BRAF inhibitors are available that are powerful in the beginning but resistance occurs rather fast. A better understanding of the underlying mechanisms of resistance is urgently needed to increase the success of the treatment. Here, we observed that in targeted therapy resistant, melanoma-derived induced pluripotent cancer cells (iPCCs) SOX2 and CD24 are upregulated. It is known that both SOX2 and CD24 expression promote an undifferentiated and cancer stem cell like phenotype, which is associated with higher therapy resistance. We therefore elucidated the role of SOX2 and CD24 in targeted therapy resistance in more detail. We found that SOX2 and CD24 are upregulated upon BRAF inhibitor treatment and that SOX2 is able to upregulate the expression of CD24 by binding to the CD24 promoter. Furthermore, we show that SOX2 or CD24 overexpression significantly increase the resistance towards BRAF inhibitors, while SOX2 knock-down rendered cell sensitive towards treatment. Moreover, CD24 and SOX2 are able to upregulate Src and STAT3 activity which could contribute to the increased resistance. Importantly, CD24 knockdown or Src inhibition in resistant SOX2 overexpressing cells, the sensitivity towards BRAF inhibitors was re-established. Hence, we suggest a novel mechanism of adaptive resistance whereby BRAF inhibition is circumvented via the upregulation of CD24 by SOX2 resulting in increased activity of Scr and STAT3. Thus, to prevent adaptive resistance it might be beneficial to use Src or STAT3 inhibitors together with MAPK pathway inhibitors.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106321 | GEO | 2018/05/15

REPOSITORIES: GEO