Year: 2017
Type: article
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.
Source: Cell Reports
Language: English
Topic: Melanoma and MAPK Pathways
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,620
Awards: Dana Farber/ Harvard Cancer Center SPORE in Gastrointestinal Cancer, G1470284823, G1682396898, G2185853629, Protein Kinase Therapeutic Targets for Non-Small Cell Lung Carcinoma, G8028275599, Functional interrogation of epigenetic vulnerabilities in KRAS-mutant pancreatic cancer, G8786459644, Regulation and function of IKKe in breast cancer initiation and maintenance
OpenAlex ID: W2586467231