title: A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility.
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.
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Loredana
authors.initials: L
authors.lastname: Vecchione
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Valentina
authors.initials: V
authors.lastname: Gambino
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Jonne
authors.initials: J
authors.lastname: Raaijmakers
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Andreas
authors.initials: A
authors.lastname: Schlicker
authors.affiliation: Cancer Genomics Netherlands, Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Arianna
authors.initials: A
authors.lastname: Fumagalli
authors.affiliation: 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.
authors.forename: Mariangela
authors.initials: M
authors.lastname: Russo
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.affiliation: Cancer Genomics Netherlands, Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Beerling
authors.affiliation: Candiolo Cancer Institute-FPO, IRCCS, SP142, Km 3.95, 10060 Candiolo, Torino, Italy.
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.affiliation: 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.
authors.forename: David G
authors.initials: DG
authors.lastname: Mollevi
authors.affiliation: Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Nizar
authors.initials: N
authors.lastname: El-Murr
authors.affiliation: Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Marielle
authors.initials: M
authors.lastname: Chiron
authors.affiliation: Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Loreley
authors.initials: L
authors.lastname: Calvet
authors.affiliation: Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Nicolazzi
authors.affiliation: Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Cécile
authors.initials: C
authors.lastname: Combeau
authors.affiliation: Sanofi Oncology, 13 Quai Jules Guesde, 94403 Vitry sur Seine, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Henry
authors.affiliation: Agendia, Science Park 406, 1098 XH Amsterdam, the Netherlands.
authors.forename: Iris M
authors.initials: IM
authors.lastname: Simon
authors.affiliation: Agendia, Science Park 406, 1098 XH Amsterdam, the Netherlands.
authors.forename: Sun
authors.initials: S
authors.lastname: Tian
authors.affiliation: Agendia, Science Park 406, 1098 XH Amsterdam, the Netherlands.
authors.forename: Sjors
authors.initials: S
authors.lastname: in 't Veld
authors.affiliation: Bioinformatics Core Facility, SIB Swiss Institute of Bioinformatics, Quartier Sorge - Batiment Genopode, 1015 Lausanne, Switzerland.
authors.forename: Giovanni
authors.initials: G
authors.lastname: D'ario
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Sara
authors.initials: S
authors.lastname: Mainardi
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Roderick L
authors.initials: RL
authors.lastname: Beijersbergen
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Cor
authors.initials: C
authors.lastname: Lieftink
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Sabine
authors.initials: S
authors.lastname: Linn
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Cornelia
authors.initials: C
authors.lastname: Rumpf-Kienzl
authors.affiliation: 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.
authors.forename: Mauro
authors.initials: M
authors.lastname: Delorenzi
authors.affiliation: Division of Molecular Carcinogenesis and Cancer Genomics Center Netherlands, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: Lodewyk
authors.initials: L
authors.lastname: Wessels
authors.affiliation: Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, 08908 Catalonia, Spain.
authors.forename: Ramon
authors.initials: R
authors.lastname: Salazar
authors.affiliation: 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.
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
authors.affiliation: 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.
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.affiliation: Cancer Genomics Netherlands, Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Jacco
authors.initials: J
authors.lastname: van Rheenen
authors.affiliation: Division of Cell Biology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, the Netherlands.
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
authors.affiliation: Molecular Digestive Oncology, University Hospitals Leuven and KU Leuven, Herestraat 49, 3000 Leuven, Belgium.
authors.forename: Sabine
authors.initials: S
authors.lastname: Tejpar
authors.affiliation: 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.
authors.forename: René
authors.initials: R
authors.lastname: Bernards
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000145:classification / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D018832:Molecular Chaperones / Q000235:genetics; D009368:Neoplasm Transplantation; D028861:Nuclear Pore Complex Proteins / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D014747:Vinblastine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000077235:Vinorelbine
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D018832:Molecular Chaperones; D028861:Nuclear Pore Complex Proteins; C094493:ran-binding protein 2; D014747:Vinblastine; D048493:Proto-Oncogene Proteins B-raf; D000077235:Vinorelbine
keywords: BRAF-like colon cancer; RANBP2; functional genomics; targeted treatment; vinorelbine