| Literature DB >> 27058664 |
Loredana Vecchione1, Valentina Gambino1, Jonne Raaijmakers2, Andreas Schlicker1, Arianna Fumagalli3, Mariangela Russo4, Alberto Villanueva5, Evelyne Beerling3, Alice Bartolini6, David G Mollevi5, Nizar El-Murr7, Marielle Chiron7, Loreley Calvet7, Céline Nicolazzi7, Cécile Combeau7, Christophe Henry7, Iris M Simon8, Sun Tian8, Sjors in 't Veld8, Giovanni D'ario9, Sara Mainardi1, Roderick L Beijersbergen1, Cor Lieftink1, Sabine Linn10, Cornelia Rumpf-Kienzl2, Mauro Delorenzi11, Lodewyk Wessels1, Ramon Salazar12, Federica Di Nicolantonio13, Alberto Bardelli13, Jacco van Rheenen3, René H Medema2, Sabine Tejpar14, René Bernards15.
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.Entities:
Keywords: BRAF-like colon cancer; RANBP2; functional genomics; targeted treatment; vinorelbine
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Year: 2016 PMID： 27058664 DOI： 10.1016/j.cell.2016.02.059
Source DB: PubMed Journal: Cell ISSN： 0092-8674 Impact factor: 41.582