Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

Perla Pucci; Liam Lee; Miao Han; Jamie D. Matthews; Leila Jahangiri; Michaela Schlederer; Eleanor Manners; Annabel Sorby-Adams; Joshua Kaggie; Ricky Trigg; Christopher Steel; Lucy Hare; Emily James; Nina Prokoph; Stephen P Ducray; Olaf Merkel; F. Rifatbegovic; Ji Luo; Sabine Taschner-Mandl; Lukas Kenner; Suzanne Turner; Amos Burke

doi:10.1038/s41467-024-47771-x

You are here:

PHAIDRA
Detail o:4418

Title (eng)

Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma

Author

Perla Pucci

Liam Lee

Miao Han

Jamie D. Matthews

Leila Jahangiri

Michaela Schlederer

Eleanor Manners

Annabel Sorby-Adams

Joshua Kaggie

Ricky Trigg

Christopher Steel

Lucy Hare

Emily James

Nina Prokoph

Stephen P Ducray

Olaf Merkel

F. Rifatbegovic

Ji Luo

Sabine Taschner-Mandl

Lukas Kenner

University of Veterinary Medicine Vienna

Suzanne Turner

Amos Burke

Abstract (eng)

Targeting Anaplastic lymphoma kinase (ALK) is a promising therapeutic strategy for aberrant ALK-expressing malignancies including neuroblastoma, but resistance to ALK tyrosine kinase inhibitors (ALK TKI) is a distinct possibility necessitating drug combination therapeutic approaches. Using high-throughput, genome-wide CRISPR-Cas9 knockout screens, we identify miR-1304-5p loss as a desensitizer to ALK TKIs in aberrant ALK-expressing neuroblastoma; inhibition of miR-1304-5p decreases, while mimics of this miRNA increase the sensitivity of neuroblastoma cells to ALK TKIs. We show that miR-1304-5p targets NRAS, decreasing cell viability via induction of apoptosis. It follows that the farnesyltransferase inhibitor (FTI) lonafarnib in addition to ALK TKIs act synergistically in neuroblastoma, inducing apoptosis in vitro. In particular, on combined treatment of neuroblastoma patient derived xenografts with an FTI and an ALK TKI complete regression of tumour growth is observed although tumours rapidly regrow on cessation of therapy. Overall, our data suggests that combined use of ALK TKIs and FTIs, constitutes a therapeutic approach to treat high risk neuroblastoma although prolonged therapy is likely required to prevent relapse.

Keywords (eng)

Cancer Therapeutic ResistanceCancer TherapyPaediatric Cancer

Type (eng)

journal article

Language

[eng]

Persistent identifier

https://phaidra.vetmeduni.ac.at/o:4418

DOI

10.1038/s41467-024-47771-x

Is in series

Title (eng)