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Cell. 2016 Apr 7;165(2):317-30. doi: 10.1016/j.cell.2016.02.059.

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

Author information

1
Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
2
Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
3
Cancer Genomics Netherlands, Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
4
Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, SP142, Km 3.95, 10060 Candiolo, Torino, Italy; FIRC Institute of Molecular Oncology (IFOM), 20139 Milano, Italy.
5
Program Against Cancer Therapeutic Resistance (ProCURE), Chemoresistance and Predictive Factors Group, Catalan Institute of Oncology (ICO) and Bellvitge Institute for Biomedical Research (IDIBELL), L'Hospitalet del Llobregat, 08908 Barcelona, Spain.
6
Candiolo Cancer Institute-FPO, IRCCS, SP142, Km 3.95, 10060 Candiolo, Torino, Italy.
7
Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
8
Agendia, Science Park 406, 1098 XH Amsterdam, the Netherlands.
9
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Quartier Sorge - Batiment Genopode, 1015 Lausanne, Switzerland.
10
Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
11
Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Quartier Sorge - Batiment Genopode, 1015 Lausanne, Switzerland; Department of Oncology, University of Lausanne, Rue de Bugnon 21, 1011 Lausanne, Switzerland; Ludwig Center for Cancer Research, University of Lausanne, Chemin des Boveresses 155, 1066 Epalinges, Switzerland.
12
Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Catalonia, Spain.
13
Department of Oncology, University of Torino, SP 142, Km 3.95, 10060 Candiolo, Torino, Italy; Candiolo Cancer Institute-FPO, IRCCS, SP142, Km 3.95, 10060 Candiolo, Torino, Italy.
14
Molecular Digestive Oncology, University Hospitals Leuven and KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
15
Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands. Electronic address: r.bernards@nki.nl.

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:

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

Comment in

PMID:
27058664
DOI:
10.1016/j.cell.2016.02.059
[Indexed for MEDLINE]
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