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New research by Professor Suzanne Turner and led by Dr Perla Pucci in her group at the Department of Pathology and Paediatric Cancer Programme, has suggested a new target for combination treatment of neuroblastoma and other cancers alongside ALK tyrosine kinase inhibitors (ALK TKI).
Resistance to ALK inhibitors is a challenge and so additional targets for treatments that can be used in combination with ALK inhibitor treatment are urgently needed.
The research, published in Nature Communications, looked at neuroblastoma cells from patients. The team screened for the genes and microRNAs or miRNAs - which are small non-coding RNAs found in all cells in the body - that are downregulated when the cells became less sensitive to ALK inhibitor treatment.
MiRNAs are often downregulated in tumour cells that are resistant to treatment, and so are becoming an attractive prospect for combination therapies. Once identified, these genes and miRNAs could be targeted for upregulation to make cells sensitive to treatment again, although upregulation of miRNAs is yet to be successfully done in trials.
The group found a range of different genes and miRNAs, some of which are already known as tumour suppressor genes in other cancers (for example, ovarian cancer or colon cancer) but highlighted a specific miRNA called miR-1304-5p as a potential desensitiser of neuroblastoma to ALK inhibitors.
The group then looked at targets of miR-1304-5p as potential treatment options.
Dr Perla Pucci, a Postdoctoral Researcher in the Turner group and lead author on the paper said: “Several different gene pathways and existing drugs were examined, but our experiments culminated in the investigation of lonafarnib.
Importantly researchers found that not only was the combination of ALK inhibitors and lonafarnib helping to improve treatment outcomes, but the mice treated in this way experienced no signs of toxicity and no signs of tumour growth.
Prof Suzanne Turner, said: “This is an exciting prospect for children with neuroblastoma as a potential treatment option to limit resistance to ALK inhibitor treatment. We look forward to working more on this and seeing the results of further research and trials.
Reference:
Pucci, P., Lee, L.C., Han, M. et al. Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma. Nat Commun 15, 3422 (2024). https://doi.org/10.1038/s41467-024-47771-x