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2 results on '"BRAF-like colon cancer"'

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

Author

Vecchione, Loredana, Gambino, Valentina, Raaijmakers, Jonne, Schlicker, Andreas, Fumagalli, Arianna, Russo, Mariangela, Villanueva, Alberto, Beerling, Evelyne, Bartolini, Alice, Mollevi, David G., El-Murr, Nizar, Chiron, Marielle, Calvet, Loreley, Nicolazzi, Céline, Combeau, Cécile, Henry, Christophe, Simon, Iris M., Tian, Sun, in ‘t Veld, Sjors, and D’ario, Giovanni

Subjects
*COLON cancer treatment, *BRAF genes, *GENETIC mutation, *GENE expression, *VINORELBINE, *THERAPEUTICS
Abstract

Summary 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. [ABSTRACT FROM AUTHOR]

Published
2016
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2. A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility

Author

Giovanni D'Ario, Sjors G J G In 't Veld, Cornelia Rumpf-Kienzl, Sabine C. Linn, Cor Lieftink, Alberto Villanueva, Andreas Schlicker, Roderick L. Beijersbergen, Christophe Henry, Jonne A. Raaijmakers, Lodewyk F. A. Wessels, Marielle Chiron, René Bernards, Jacco van Rheenen, Sara Mainardi, Mariangela Russo, Alice Bartolini, Loredana Vecchione, Cecile Combeau, Mauro Delorenzi, David G. Molleví, Iris Simon, Ramon Salazar, Federica Di Nicolantonio, Alberto Bardelli, Sabine Tejpar, René H. Medema, Céline Nicolazzi, Evelyne Beerling, Arianna Fumagalli, Valentina Gambino, Loreley Calvet, Nizar El-Murr, Sun Tian, and Hubrecht Institute for Developmental Biology and Stem Cell Research

Subjects
Genetics and Molecular Biology (all), 0301 basic medicine, endocrine system diseases, Mutant, BRAF-like colon cancer, medicine.disease_cause, Microtubules, Biochemistry, Small hairpin RNA, Mice, 0302 clinical medicine, Non-U.S. Gov't, skin and connective tissue diseases, Cells, Cultured, Mutation, Research Support, Non-U.S. Gov't, 3. Good health, targeted treatment, 030220 oncology & carcinogenesis, Colonic Neoplasms, Heterografts, functional genomics, Proto-Oncogene Proteins B-raf, Mice, Nude, Biology, Vinblastine, Research Support, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Microtubule, medicine, Journal Article, Animals, Humans, Gene silencing, Mitosis, neoplasms, Biochemistry, Genetics and Molecular Biology(all), fungi, Antineoplastic Agents, Phytogenic, digestive system diseases, Nuclear Pore Complex Proteins, vinorelbine, RANBP2, Biochemistry, Genetics and Molecular Biology (all), 030104 developmental biology, Cancer research, Neoplasm Transplantation, V600E, Molecular Chaperones, Genetics and Molecular Biology(all), Genetic screen
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.

Published
2016

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