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

Details

Serval ID
serval:BIB_482D42C5A0C1
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility.
Journal
Cell
Author(s)
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., D'ario G., Mainardi S., Beijersbergen R.L., Lieftink C., Linn S., Rumpf-Kienzl C., Delorenzi M., Wessels L., Salazar R., Di Nicolantonio F., Bardelli A., van Rheenen J., Medema R.H., Tejpar S., Bernards R.
ISSN
1097-4172 (Electronic)
ISSN-L
0092-8674
Publication state
Published
Issued date
2016
Peer-reviewed
Oui
Volume
165
Number
2
Pages
317-330
Language
english
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.
Keywords
Animals, Antineoplastic Agents, Phytogenic/administration & dosage, Antineoplastic Agents, Phytogenic/pharmacology, Cells, Cultured, Colonic Neoplasms/classification, Colonic Neoplasms/drug therapy, Heterografts, Humans, Mice, Mice, Nude, Microtubules/drug effects, Microtubules/metabolism, Molecular Chaperones/genetics, Neoplasm Transplantation, Nuclear Pore Complex Proteins/genetics, Proto-Oncogene Proteins B-raf/genetics, Vinblastine/administration & dosage, Vinblastine/analogs & derivatives
Pubmed
Web of science
Open Access
Yes
Create date
15/05/2016 14:14
Last modification date
20/08/2019 13:54
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