Nejvíce citovaný článek - PubMed ID 15958613
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.
- MeSH
- anaplastická lymfomová kináza * genetika metabolismus antagonisté a inhibitory MeSH
- apoptóza účinky léků genetika MeSH
- chemorezistence genetika účinky léků MeSH
- dibenzocyklohepteny * MeSH
- farnesyltranstransferasa * antagonisté a inhibitory metabolismus MeSH
- GTP-fosfohydrolasy * genetika metabolismus MeSH
- inhibitory proteinkinas * farmakologie terapeutické užití MeSH
- lidé MeSH
- membránové proteiny metabolismus genetika MeSH
- mikro RNA * genetika metabolismus MeSH
- mutace MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- neuroblastom * farmakoterapie genetika patologie metabolismus MeSH
- piperidiny * farmakologie terapeutické užití MeSH
- pyridiny * farmakologie terapeutické užití MeSH
- regulace genové exprese u nádorů účinky léků MeSH
- synergismus léků MeSH
- xenogenní modely - testy antitumorózní aktivity MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- ALK protein, human MeSH Prohlížeč
- anaplastická lymfomová kináza * MeSH
- dibenzocyklohepteny * MeSH
- farnesyltranstransferasa * MeSH
- GTP-fosfohydrolasy * MeSH
- inhibitory proteinkinas * MeSH
- lonafarnib MeSH Prohlížeč
- membránové proteiny MeSH
- mikro RNA * MeSH
- NRAS protein, human MeSH Prohlížeč
- piperidiny * MeSH
- pyridiny * MeSH