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

Belinda Wang1, Elsa Beyer Krall1, Andrew James Aguirre1

  • 1Department 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.

Cell Reports
|February 9, 2017
PubMed

Insights

Intrinsic resistance to MEK and RAF inhibitors (MAPKi) in cancer can be overcome. Loss of CIC or ATXN1L, or increased ETV factors, impacts MAPKi effectiveness, revealing a new therapeutic axis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Targeted therapies like MEK and RAF inhibitors (MAPKi) show limited effectiveness in RAS- and RAF-mutant cancers due to intrinsic resistance and pathway reactivation.
  • Understanding resistance mechanisms is crucial for improving cancer treatment outcomes.

Purpose of the Study:

  • To identify genes that modulate sensitivity to MAPKi in RAS-mutant cancers.
  • To elucidate the role of the ATXN1L-CIC-ETS transcription factor axis in MAPKi resistance.

Main Methods:

  • Genome-scale CRISPR-Cas9 loss-of-function screens were performed in KRAS mutant pancreatic cancer cell lines treated with trametinib.
  • Analysis of CIC, ATXN1L, and ETV factors' impact on cancer cell survival and drug sensitivity.
  • Correlation of ATXN1L expression with clinical response to MAPKi.

Main Results:

  • Loss of CIC, a repressor of ETV1, ETV4, and ETV5, promoted cancer cell survival during MAPKi treatment.
  • ATXN1L deletion or ETV1/4/5 overexpression modulated sensitivity to trametinib.
  • ATXN1L expression inversely correlated with patient response to MAPKi therapy.

Conclusions:

  • The ATXN1L-CIC-ETS transcription factor axis is identified as a key mediator of resistance to MAPKi.
  • Targeting this axis may offer new therapeutic strategies for RAS- and RAF-mutant cancers.
  • Further research into this pathway could enhance the efficacy of existing targeted therapies.
Keywords:
ATXN1LCICCRISPR-Cas9ETSKRASMAPKMEKcancerresistancetrametinib

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