The RAS-MAPK pathway in neuroblastoma

Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system. It occurs mainly in young children, with a median age of 17 months and has an estimated incidence of 1,1:100.000. Primary neuroblastoma tumors generally respond quite well to chemotherapy. However, a significant part of these, about 25%, relapse and subsequently show resistance to treatment.
In this thesis we describe the results of Whole Genome Sequencing of relapse neuroblastoma tumors. We show that these tumors are derived from the corresponding primary tumors and that clonal selection occurs between the primary and the relapse tumor. We also show that mutations affecting the RAS-MAPK pathway occur at a very high frequency (78%) in these relapses and that the presence of these mutations is associated with sensitivity to MEK inhibitors, both in vitro and in vivo. The role of this pathway in neuroblastoma is further explored throughout this thesis.
Firstly, we show through a gene signature that activation of this pathway is associated with poor prognosis and the presence of known and novel mutations. Moreover, activation of this pathway causes a significant growth increase in neuroblastoma xenograft tumors.
Secondly, we discover through high-throughput screening that combining MEK inhibitors with Bcl2 family inhibitors shows promising results in RAS-MAPK mutated neuroblastoma cell lines. Finally, we use our gene signature to gain some more insight into the role of this pathway in neuroblastoma and review preclinical data on the RAS-MAPK pathway as a target for therapy in pediatric solid tumors.