The development of mutant BRAF inhibitors has improved the outcome for melanoma patients with BRAF
V600E
mutations. Although the initial response to these inhibitors can be dramatic, sometimes resulting in complete tumor regression, the majority of melanomas become resistant. To study resistance to BRAF inhibition, we developed a novel mouse model of melanoma using a tetracycline/doxycycline-regulated system that permits control of mutant BRAF expression. Treatment with doxycycline leads to loss of mutant BRAF expression and tumor regression, but tumors recur after a prolonged period of response to treatment. Vemurafenib, encorafenib and dabrafenib induce cell cycle arrest and apoptosis in BRAF melanoma cell lines; however, a residual population of tumor cells survive. Comparing gene expression in human cell lines and mouse tumors can assist with the identification of novel mechanisms of resistance. Accordingly, we conducted RNA sequencing analysis and immunoblotting on untreated and doxycycline-treated dormant mouse melanomas and human mutant BRAF melanoma cell lines treated with 2 μM vemurafenib for 20 days. We found conserved expression changes in histone methyltransferase genes
ASH2, EZH2
,
PRMT5, SUV39H1, SUV39H2,
and
SYMD2
in P-ERK low, p-38 high melanoma cells following prolonged BRAF inhibition. Quantitative mass spectrometry, determined a corresponding reduction in histone Lys9 and Lys27 methylation and increase in Lys36 methylation in melanoma cell lines treated with 2 μM vemurafenib for 20 days. Thus, these changes as are part of the initiate response to BRAF inhibition and likely contribute to the survival of melanoma cells.
Glioblastoma multiforme (GBM) is a primary brain tumor with a high mortality rate and a median survival time of ~14 months from the initial diagnosis. Although progress has been made in the currently available therapies, the treatment of GBM remains palliative. GBM contains subsets of GBM stem cells (GSCs) that share numerous neural stem/progenitor cell characteristics, such as expression of stem cell markers, self-renewal and multi-lineage differentiation capacity, thus contributing to the heterogeneity and complexity of these tumors. GSCs are potentially associated with tumor initiation and they are considered as the driving force behind tumor formation, as they possess tumor-propagating potential and exhibit preferential resistance to radiotherapy and chemotherapy. Targeting self-renewal signaling pathways in cancer stem cells may effectively reduce tumor recurrence and significantly improve prognosis. The aim of the present review was to summarize the current knowledge on the self-renewal signaling pathways of GSCs and discuss potential future targeting strategies for the design of differentiation therapies.
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