ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition

Belinda Wang; Elsa Beyer Krall; Andrew James Aguirre; Miju Kim; Hans Ragnar Widlund; Mihir Bhavik Doshi; Ewa Sicinska; Rita Sulahian; Amy Goodale; Glenn Spencer Cowley; Federica Piccioni; John Gerard Doench; David Edward Root; William Chun Hahn

doi:10.1016/j.celrep.2017.01.031

Cell Reports (Feb 2017)

ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition

Belinda Wang,
Elsa Beyer Krall,
Andrew James Aguirre,
Miju Kim,
Hans Ragnar Widlund,
Mihir Bhavik Doshi,
Ewa Sicinska,
Rita Sulahian,
Amy Goodale,
Glenn Spencer Cowley,
Federica Piccioni,
John Gerard Doench,
David Edward Root,
William Chun Hahn

Affiliations

Belinda Wang: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Elsa Beyer Krall: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Andrew James Aguirre: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Miju Kim: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Hans Ragnar Widlund: Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115, USA
Mihir Bhavik Doshi: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Ewa Sicinska: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Rita Sulahian: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Amy Goodale: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Glenn Spencer Cowley: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
Federica Piccioni: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
John Gerard Doench: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
David Edward Root: Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA
William Chun Hahn: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA

DOI: https://doi.org/10.1016/j.celrep.2017.01.031
Journal volume & issue: Vol. 18, no. 6
pp. 1543 – 1557

Abstract

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Intrinsic resistance and RTK-RAS-MAPK pathway reactivation has limited the effectiveness of MEK and RAF inhibitors (MAPKi) in RAS- and RAF-mutant cancers. To identify genes that modulate sensitivity to MAPKi, we performed genome-scale CRISPR-Cas9 loss-of-function screens in two KRAS mutant pancreatic cancer cell lines treated with the MEK1/2 inhibitor trametinib. Loss of CIC, a transcriptional repressor of ETV1, ETV4, and ETV5, promoted survival in the setting of MAPKi in cancer cells derived from several lineages. ATXN1L deletion, which reduces CIC protein, or ectopic expression of ETV1, ETV4, or ETV5 also modulated sensitivity to trametinib. ATXN1L expression inversely correlates with response to MAPKi inhibition in clinical studies. These observations identify the ATXN1L-CIC-ETS transcription factor axis as a mediator of resistance to MAPKi.

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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