Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma PMID: 38653965

ADC Targets in Oncology

2026-04-10

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

Nat Commun. 2024 Apr 23;15(1):3422. doi: 10.1038/s41467-024-47771-x.

Perla Pucci ¹ , Liam C Lee ¹ ² , Miaojun Han ¹ ³ , Jamie D Matthews ¹ , Leila Jahangiri ¹ ⁴ ⁵ , Michaela Schlederer ⁶ , Eleanor Manners ¹ ⁷ , Annabel Sorby-Adams ⁸ ⁹ , Joshua Kaggie ¹⁰ , Ricky M Trigg ¹ ¹¹ , Christopher Steel ¹ , Lucy Hare ¹ ¹² , Emily R James ¹ , Nina Prokoph ¹ , Stephen P Ducray ¹ , Olaf Merkel ¹³ ¹⁴ , Firkret Rifatbegovic ¹⁵ , Ji Luo ¹⁶ , Sabine Taschner-Mandl ¹⁵ , Lukas Kenner ¹³ ¹⁴ ¹⁷ ¹⁸ ¹⁹ , G A Amos Burke ¹² , Suzanne D Turner ²⁰ ²¹ ²²

Affiliations

1. Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK.
2. Merck & Co, 2000 Galloping Hill Rd, Kenilworth, NJ, 07033, USA.
3. OncoSec, San Diego, CA, 92121, USA.
4. Department of Life Sciences, Birmingham City University, Birmingham, UK.
5. Nottingham Trent University, School of Science & Technology, Clifton Lane, Nottingham, NG11 8NS, UK.
6. Department of Pathology, Division of Experimental and Translational Pathology, Medical University of Vienna, 1090, Vienna, Austria.
7. Chelsea and Westminster Hospital, NHS Foundation Trust, London, SW10 9NH, UK.
8. MRC Mitochondrial Biology Unit, University of Cambridge, The Keith Peters Building, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0XY, UK.
9. Department of Medicine, University of Cambridge, Addenbrookes Hospital, Hills Road, Cambridge, CB2 0QQ, UK.
10. Department of Radiology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0QQ, UK.
11. Functional Genomics, GlaxoSmithKline, Stevenage, SG1 2NY, UK.
12. Department of Paediatric Haematology, Oncology and Palliative Care, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK.
13. Department of Pathology, Medical University of Vienna, Vienna, 1090, Austria.
14. European Research Initiative for ALK related malignancies (ERIA), Cambridge, CB2 0QQ, UK.
15. St. Anna Children's Cancer Research Institute, CCRI, Zimmermannplatz 10, 1090, Vienna, Austria.
16. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA.
17. Unit of Laboratory Animal Pathology, University of Veterinary Medicine Vienna, Vienna, Austria.
18. Center for Biomarker Research in Medicine (CBmed), Graz, Austria.
19. Christian Doppler Laboratory for Applied Metabolomics (CDL-AM), Medical University of Vienna, Vienna, Austria.
20. Department of Pathology, Division of Cellular and Molecular Pathology, University of Cambridge, Cambridge, CB20QQ, UK. [email protected].
21. European Research Initiative for ALK related malignancies (ERIA), Cambridge, CB2 0QQ, UK. [email protected].
22. Faculty of Medicine, Masaryk University, Brno, Czech Republic. [email protected].

Abstract

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.