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

Cell Reports

Amy Goodale¹  Glenn Spencer Cowley¹  David Edward Root¹  Federica Piccioni¹  John Gerard Doench¹  Hans Ragnar Widlund²  Belinda Wang³  William Chun Hahn³  Elsa Beyer Krall³  Andrew James Aguirre³  Rita Sulahian³  Ewa Sicinska³  Mihir Bhavik Doshi³  Miju Kim³ 

[1] Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA;Department of Dermatology, Brigham and Women’s Hospital, Boston, MA 02115, USA;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA;

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

DOI  :  10.1016/j.celrep.2017.01.031

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown