A Vulnerability of a Subset of Colon Cancers with Potential Clinical Utility | Zendy

Loredana Vecchione | Zendy; Valentina Gambino | Zendy; Jonne A. Raaijmakers | Zendy; Andreas Schlicker | Zendy; Arianna Fumagalli | Zendy; Mariangela Russo | Zendy; Alberto Villanueva | Zendy; Evelyne Beerling | Zendy; Alice Bartolini | Zendy; David G. Mollevı́ | Zendy; Nizar El-Murr | Zendy; Marielle Chiron | Zendy; Loreley Calvet | Zendy; Céline Nicolazzi | Zendy; Cécile Combeau | Zendy; Christophe Henry | Zendy; Iris Simón | Zendy; Sun Tian | Zendy; Sjors G. J. G. In ‘t Veld | Zendy; Giovanni D’Ario | Zendy; Sara Mainardi | Zendy; Roderick L. Beijersbergen | Zendy; Cor Lieftink | Zendy; Sabine C. Linn | Zendy; Cornelia Rumpf-Kienzl | Zendy; Mauro Delorenzi | Zendy; Lodewyk F.A. Wessels | Zendy; Ramón Salazar | Zendy; Federica Di Nicolantonio | Zendy; Alberto Bardelli | Zendy; Jacco van Rheenen | Zendy; René H. Medema | Zendy; Sabine Tejpar | Zendy; René Bernards | Zendy

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

Author(s) -

Loredana Vecchione,

Valentina Gambino,

Jonne A. Raaijmakers,

Andreas Schlicker,

Arianna Fumagalli,

Mariangela Russo,

Alberto Villanueva,

Evelyne Beerling,

Alice Bartolini,

David G. Mollevı́,

Nizar El-Murr,

Marielle Chiron,

Loreley Calvet,

Céline Nicolazzi,

Cécile Combeau,

Christophe Henry,

Iris Simón,

Sun Tian,

Sjors G. J. G. In ‘t Veld,

Giovanni D’Ario,

Sara Mainardi,

Roderick L. Beijersbergen,

Cor Lieftink,

Sabine C. Linn,

Cornelia Rumpf-Kienzl,

Mauro Delorenzi,

Lodewyk F.A. Wessels,

Ramón Salazar,

Federica Di Nicolantonio,

Alberto Bardelli,

Jacco van Rheenen,

René H. Medema,

Sabine Tejpar,

René Bernards

Publication year - 2016

Publication title -

cell

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 26.304

H-Index - 776

eISSN - 1097-4172

pISSN - 0092-8674

DOI - 10.1016/j.cell.2016.02.059

Subject(s) - biology , cancer research , gene silencing , vinorelbine , mitosis , small hairpin rna , mitotic catastrophe , microbiology and biotechnology , cancer , genetics , gene , cancer cell , gene knockdown , chemotherapy , cisplatin

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.

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