A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility

Loredana Vecchione, Valentina Gambino, Jonne Raaijmakers, Andreas Schlicker, Arianna Fumagalli, Mariangela Russo, Alberto Villanueva, Evelyne Beerling, Alice Bartolini, David G. Mollevi, Nizar El-Murr, Marielle Chiron, Loreley Calvet, Céline Nicolazzi, Cécile Combeau, Christophe Henry, Iris M. Simon, Sun Tian, Sjors In 'T Veld, Giovanni D'ArioSara Mainardi, Roderick L. Beijersbergen, Cor Lieftink, Sabine C. Linn, Cornelia Rumpf-Kienzl, Mauro Delorenzi, Lodewyk F A Wessels, Ramon Salazar, Federica Di Nicolantonio, Alberto Bardelli, Jacco Van Rheenen, René H. Medema, Sabine Tejpar, Rene Bernards

Research output: Contribution to journalArticle

Abstract

BRAF(V600E) mutant colon cancers (CCs) have a characteristic gene expression signature that is also found in some tumors lacking this mutation. Collectively, they are referred to as "BRAF-like" tumors and represent some 20% of CCs. We used a shRNA-based genetic screen focused on genes upregulated in BRAF(V600E) CCs to identify vulnerabilities of this tumor subtype that might be exploited therapeutically. Here, we identify RANBP2 (also known as NUP358) as essential for survival of BRAF-like, but not for non-BRAF-like, CC cells. Suppression of RANBP2 results in mitotic defects only in BRAF-like CC cells, leading to cell death. Mechanistically, RANBP2 silencing reduces microtubule outgrowth from the kinetochores, thereby inducing spindle perturbations, providing an explanation for the observed mitotic defects. We find that BRAF-like CCs display far greater sensitivity to the microtubule poison vinorelbine both in vitro and in vivo, suggesting that vinorelbine is a potential tailored treatment for BRAF-like CCs.

Original languageEnglish
Pages (from-to)317-330
Number of pages14
JournalCell
Volume165
Issue number2
DOIs
Publication statusPublished - Apr 7 2016

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Keywords

  • BRAF-like colon cancer
  • functional genomics
  • RANBP2
  • targeted treatment
  • vinorelbine

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Vecchione, L., Gambino, V., Raaijmakers, J., Schlicker, A., Fumagalli, A., Russo, M., Villanueva, A., Beerling, E., Bartolini, A., Mollevi, D. G., El-Murr, N., Chiron, M., Calvet, L., Nicolazzi, C., Combeau, C., Henry, C., Simon, I. M., Tian, S., In 'T Veld, S., ... Bernards, R. (2016). A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility. Cell, 165(2), 317-330. https://doi.org/10.1016/j.cell.2016.02.059