Page 180 - Molecular features of low-grade developmental brain tumours

7
CHAPTER 7
found between the two groups, although it must be noted that these differences are small and only detectible with quantification. In chapter 4, we show that the MAPK pathway could be of interest as a target for treatment. Therefore, the differences in methylation of the ERK/MAPK pathway between the two groups are interesting and could potentially reflect treatment response of SEGAs to ERK/MAPK inhibitors. However, the precise role of the ERK/ MAPK pathway in defining these two groups remains elusive and ERK/MAPK inhibitors are not routinely used as treatment for SEGAs, limiting the possibility to evaluate this hypothesis. Furthermore, none of the other available clinical data could explain the subgroups. However, it is possible that these groups reflect important clinical features that were not evaluated in this thesis and thus, deserve further investigation in more retrospective studies.
Figure 2. Robustness of the two SEGA groups in extended cohort of SEGAs. a. TSNE plot and b. heatmap with a total of 92 SEGAs including the 42 SEGA samples from chapter 3, showing the
robustness of the two SEGA groups identified.
MAPK pathway in SEGA
Since the ERK/MAPK pathway is often affected in pLGGs and was identified as an important pathway in SEGAs in chapters 3 & 4 we decided to focus on this pathway for further analysis, in chapter 4. In accordance with previous studies, we show that MAPK activation is present in tubers and SEGAs. Additionally, we show that the activation of MAPK in SEGAs seems to be independent of TSC1/TSC2 mutation and LOH. MAPK/ERK activation can result in TSC2 phosphorylation and thereby increase mTORC1 activation, indicating that these two pathways are intrinsically linked 54-56. Moreover, inhibition of mTORC1 leads to the disruption of the negative feedback on the MAPK/ERK pathway resulting in MAPK/ERK activation in human cancer and TSC-deficient cells 57,58. Therefore, dual targeting of mTORC1 and MAPK pathways in SEGA and other TSC lesions may have advantages in treatment for patients with TSC. In accordance with previous research, we found that inhibiting the MAPK/ERK pathway with the MAPK inhibitor U0126 decreased the proliferation of primary SEGA cells 51,57,59. In contrast, we did not observe differences between rapamycin and combined therapy with rapamycin and the ERK inhibitor U0126 in a SEGA-derived cell culture 51,57. However, in previous studies suppression of both the mTORC1 and MAPK/ERK pathway was most efficient in decreasing
178