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

Perla Pucci Perla Pucci Liam Lee Liam Lee Miao Han Miao Han Jamie D. Matthews Jamie D. Matthews Leila Jahangiri Leila Jahangiri Michaela Schlederer Michaela Schlederer Eleanor Manners Eleanor Manners Annabel Sorby-Adams Annabel Sorby-Adams Joshua Kaggie Joshua Kaggie Ricky Trigg Ricky Trigg Christopher Steel Christopher Steel Lucy Hare Lucy Hare Emily James Emily James Nina Prokoph Nina Prokoph Stephen P Ducray Stephen P Ducray Olaf Merkel Olaf Merkel F. Rifatbegovic F. Rifatbegovic Ji Luo Ji Luo Sabine Taschner-Mandl Sabine Taschner-Mandl Lukas Kenner Lukas Kenner Suzanne Turner Suzanne Turner Amos Burke Amos Burke Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma Nature Publishing Group 2024 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. PDFDocument eng 2025-09-22T15:33:00.744171Z 2024 Cancer Therapeutic Resistance Cancer Therapy Paediatric Cancer 3396545 b application/pdf http://creativecommons.org/licenses/by/4.0/