Poster Presentation 38th Lorne Cancer Conference 2026

Exploring the functional and therapeutic impacts of cbl mutations in paediatric solid and brain tumours (#126)

Katherine Camper 1 , Chelsea Mayoh 1 2 , Gabor Tax 1 2 , Pablo Acera Mateos 1 2 , Wenyan Li 1 2 , Sam El-Kamand 1 2 , Patricia Sullivan 1 2 , James Bradley 1 2 , Teresa Sadras 3 4 , Robert Salomon 1 2 , Marie Wong 1 2 , Mark J. Cowley 1 2 , Antoine de Weck 1 2 , Loretta M.S. Lau 1 2 5 , Neevika Manoharan 1 2 5 , Paul G. Ekert 1 2 3 4 , Lauren M. Brown 1 2
  1. Children's Cancer Institute, Kensington, NSW, Australia
  2. School of Clinical Medicine, UNSW Sydney , Sydney , NSW, Australia
  3. Peter MacCallum Cancer Centre, Parkville, VIC, Australia
  4. The Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, Australia
  5. Kids Cancer Centre, Sydney Children's Hospital, Randwick, NSW, Australia

Genomics offers insights into the drivers of childhood cancer. Through the analysis of molecular data from patients enrolled in the ZERO childhood cancer program (ZERO), we have identified an unexpected distribution of mutations in CBL in paediatric cancer patients [1]. CBL is an E3 ubiquitin ligase that negatively regulates receptor tyrosine kinases (RTKs) and potentiates intracellular signalling [2]. The oncogenic effects of CBL mutations have been extensively characterised in haematological malignancies and we have recently shown that the established CBL ex8/9Δ variant is RTK-activating in neuroblastoma [3]. However, the impacts of CBL variants in other paediatric cancers are unknown. 

Through the analysis of ZERO whole genome and transcriptomic (RNAseq) sequencing data, we have identified a range of known and novel CBL mutations in paediatric solid and brain tumours (n=16). These include the CBL ex8/9Δ variant in 1 neuroblastoma and 1 germ cell tumour sample, as previously reported. We have since demonstrated that expression of CBL ex8/9Δ variant in ALK or NRAS-dependent neuroblastoma cell lines can drive resistance to ALK or MEK inhibition, suggesting the ability to activate alternate RTK or intracellular signalling pathways to overcome the loss of ALK or MAPK pathway signalling in these cell lines. 

The majority of CBL variants were identified in brain tumour samples and included either CBL missense (n=8) or splice (n=6) variants. Analysis of CBL isoform expression using RNAseq data or PCR-based methods confirmed that CBL splice variants resulted in exclusion of either exon 8 (ex8Δ), exon 9 (ex9Δ) or a partial loss of exon 8 (E366_E373). We have now generated cell line models of 12 CBL variants, including 4 intragenic deletion variants (ex8/9Δ, ex8Δ, ex9Δ, E366_E373) and 8 missense mutations, the majority of which are novel or variants of uncertain significance (6/8). We will apply unbiased single-cell transcriptomics, phosphoproteomics, and drug screening approaches to these models to further investigate the functional and therapeutic impacts of CBL variants.  

We have shown that CBL mutations may represent a novel class of RTK-activating events in paediatric patients with non-haematological tumours who might benefit from RTK-targeted therapies. 

  1. Wong, M., et al., Whole genome, transcriptome and methylome profiling enhances actionable target discovery in high-risk pediatric cancer. Nature Medicine, 2020. 26(11): p. 1742-1753.
  2. Thien, C.B.F. and W.Y. Langdon, Cbl: many adaptations to regulate protein tyrosine kinases. Nature Reviews Molecular Cell Biology, 2001. 2(4): p. 294-307.
  3. Brown, L.M., et al., Abstract 1770: Right oncogene, wrong tumor - CBL mutations in pediatric CNS and solid tumors. Cancer Research, 2024. 84(6_Supplement): p. 1770-1770.