<oai_dc:dc xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:oai_dc="http://www.openarchives.org/OAI/2.0/oai_dc/" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xsi:schemaLocation="http://www.openarchives.org/OAI/2.0/oai_dc/ http://www.openarchives.org/OAI/2.0/oai_dc.xsd">
  <dc:title xml:lang="eng">Targeting NRAS via miR-1304-5p or farnesyltransferase inhibition confers sensitivity to ALK inhibitors in ALK-mutant neuroblastoma</dc:title>
  <dc:language>eng</dc:language>
  <dc:format>application/pdf</dc:format>
  <dc:type xml:lang="ita">Testo</dc:type>
  <dc:type xml:lang="ita">Articolo di rivista</dc:type>
  <dc:type xml:lang="eng">Text</dc:type>
  <dc:type xml:lang="eng">journal article</dc:type>
  <dc:subject xml:lang="eng">Cancer Therapeutic Resistance</dc:subject>
  <dc:subject xml:lang="eng">Cancer Therapy</dc:subject>
  <dc:subject xml:lang="eng">Paediatric Cancer</dc:subject>
  <dc:creator>Perla Pucci</dc:creator>
  <dc:creator>Liam Lee</dc:creator>
  <dc:creator>Miao Han</dc:creator>
  <dc:creator>Jamie D. Matthews</dc:creator>
  <dc:creator>Leila Jahangiri</dc:creator>
  <dc:creator>Michaela Schlederer</dc:creator>
  <dc:creator>Eleanor Manners</dc:creator>
  <dc:creator>Annabel Sorby-Adams</dc:creator>
  <dc:creator>Joshua Kaggie</dc:creator>
  <dc:creator>Ricky Trigg</dc:creator>
  <dc:creator>Christopher Steel</dc:creator>
  <dc:creator>Lucy Hare</dc:creator>
  <dc:creator>Emily James</dc:creator>
  <dc:creator>Nina Prokoph</dc:creator>
  <dc:creator>Stephen P Ducray</dc:creator>
  <dc:creator>Olaf Merkel</dc:creator>
  <dc:creator>F. Rifatbegovic</dc:creator>
  <dc:creator>Ji Luo</dc:creator>
  <dc:creator>Sabine Taschner-Mandl</dc:creator>
  <dc:creator>Lukas Kenner</dc:creator>
  <dc:creator>Suzanne Turner</dc:creator>
  <dc:creator>Amos Burke</dc:creator>
  <dc:description xml:lang="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.</dc:description>
  <dc:rights>http://creativecommons.org/licenses/by/4.0/</dc:rights>
  <dc:type xml:lang="deu">Text</dc:type>
  <dc:type xml:lang="deu">Wissenschaftlicher Artikel</dc:type>
  <dc:publisher>Nature Publishing Group</dc:publisher>
  <dc:identifier>doi:10.1038/s41467-024-47771-x</dc:identifier>
  <dc:rights xml:lang="eng">Copyright © 2024, The Author(s)</dc:rights>
  <dc:rights xml:lang="eng">open access</dc:rights>
  <dc:source xml:lang="eng">Nature Communications</dc:source>
  <dc:date>2024</dc:date>
  <dc:identifier>https://phaidra.vetmeduni.ac.at/o:4418</dc:identifier>
</oai_dc:dc>