1. A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility.
- Author
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Vecchione L, Gambino V, Raaijmakers J, Schlicker A, Fumagalli A, Russo M, Villanueva A, Beerling E, Bartolini A, Mollevi DG, El-Murr N, Chiron M, Calvet L, Nicolazzi C, Combeau C, Henry C, Simon IM, Tian S, in 't Veld S, D'ario G, Mainardi S, Beijersbergen RL, Lieftink C, Linn S, Rumpf-Kienzl C, Delorenzi M, Wessels L, Salazar R, Di Nicolantonio F, Bardelli A, van Rheenen J, Medema RH, Tejpar S, and Bernards R
- Subjects
- Animals, Antineoplastic Agents, Phytogenic administration & dosage, 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 pharmacology, Vinorelbine, Antineoplastic Agents, Phytogenic pharmacology, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Vinblastine analogs & derivatives
- 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., (Copyright © 2016 Elsevier Inc. All rights reserved.)
- Published
- 2016
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