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

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

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

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Animals
Antigens, Protozoan / genetics
Antigens, Protozoan / metabolism*
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics
Drug Resistance, Neoplasm / physiology
HCT116 Cells
Humans
MAP Kinase Signaling System / drug effects*
MAP Kinase Signaling System / genetics
MAP Kinase Signaling System / physiology*
Mice
Mutation / genetics
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins p21(ras) / genetics
Proto-Oncogene Proteins p21(ras) / metabolism
Pyridones / pharmacology
Pyrimidinones / pharmacology
Repressor Proteins / genetics
Repressor Proteins / metabolism*
Transcription Factors / genetics
Transcription Factors / metabolism*
raf Kinases / genetics
raf Kinases / metabolism

Substances

ATXN1L protein, human
Antigens, Protozoan
CIC protein, human
Protein Kinase Inhibitors
Pyridones
Pyrimidinones
Repressor Proteins
Transcription Factors
Eimeria tenella sporozoite antigen
trametinib
raf Kinases
Proto-Oncogene Proteins p21(ras)

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

Authors

Affiliations

Abstract

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MeSH terms

Substances

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