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Cell Rep. 2017 Feb 7;18(6):1543-1557. doi: 10.1016/j.celrep.2017.01.031.

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

Author information

1
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
2
Department of Dermatology, Brigham and Women's Hospital, Boston, MA 02115, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Center for Molecular Oncologic Pathology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
5
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: william_hahn@dfci.harvard.edu.

Abstract

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.

KEYWORDS:

ATXN1L; CIC; CRISPR-Cas9; ETS; KRAS; MAPK; MEK; cancer; resistance; trametinib

PMID:
28178529
PMCID:
PMC5313047
DOI:
10.1016/j.celrep.2017.01.031
[Indexed for MEDLINE]
Free PMC Article

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