Molecularly targeted therapies improve outcomes for childhood cancer patients and are made possible by precision medicine approaches like the Zero Childhood Cancer Program (ZERO). Mutations in CBL, an E3 ubiquitin ligase, represent one such molecular target in acute myeloid leukaemia, where CBL mutation mediates activation of the Receptor Tyrosine Kinase (RTK) FLT3 and sensitivity to FLT3-targeted Tyrosine Kinase Inhibitors (TKIs). We have identified novel CBL mutations in paediatric CNS and solid tumours, raising the possibility that CBL mutations mediate RTK activation in other tumour types and these patients may benefit from TKI therapy.
We analysed whole genome and RNA sequencing data from the ZERO cohort and identified 30 somatic variants in 26 individual patients, including 16 with CNS tumours and 2 with other solid tumours. Fifteen non-haematological tumour samples harboured CBL mutations that are established drivers (CBL exon 8/9Δ) or suspected to be oncogenic given their location in critical functional domains, the linker region or RING finger, and in silico pathogenicity analysis. Over half of these samples had molecular indications (e.g. RTK ligand overexpression) of RTK activation (9/15). Most CNS tumours did not fall into a pre-defined DNA methylation-based subtype classification, suggesting that CBL mutation may represent a distinct molecular entity. In vitro modelling of CBL mutations in non-haematological tumour cell lines (e.g. neuroblastoma and high-grade glioma) demonstrated that CBL mutations can block CBL mediated degradation of RTKs resulting in maintained RTK signalling in other tumour types.
In this study, we show that CBL mutation may be a marker of RTK activation and therapeutic target in paediatric CNS and solid tumours. This finding will extend the benefit of TKIs, which have proven efficacy in paediatric cancer, to more patients.