biostudies-literatureLlaurado Fernandez MJanet D. Cottrelle FoundationVGH and UBC Hospital FoundationBC Cancer FoundationWomen's Health Research InstituteCure Our Ovarian CancerOvarian Cancer CanadaChinese Scholarship CouncilOncode Institute1862-1874https://www.ebi.ac.uk/biostudies/studies/S-EPMC9716250biostudies-literatureUnknown21(12)Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies. Both gain-of-function and loss-of-function CRISPR-Cas9 genome-wide libraries were used to screen LGSOC cell lines to identify genes that modulate the response to MEKi. Overexpression of MAML2 and loss of MAP3K1 were identified, both leading to overexpression of the NOTMolecular cancer therapeuticsNOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition.PMC9716250877290Hijmans EMHoenisch JBittner MCarey MSKim HWisman GBAWong NKYLok CARLieftink CBernards RBerns KDiMattia GEBeijersbergen RLLi SLee CHGennissen AMCLlaurado Fernandez MHamilton ADawson Ade Jong SfalseNOTCH Signaling Limits the Response of Low-Grade Serous Ovarian Cancers to MEK Inhibition.Low-grade serous ovarian cancer (LGSOC) is a rare subtype of epithelial ovarian cancer with high fatality rates in advanced stages due to its chemoresistant properties. LGSOC is characterized by activation of MAPK signaling, and recent clinical trials indicate that the MEK inhibitor (MEKi) trametinib may be a good treatment option for a subset of patients. Understanding MEKi-resistance mechanisms and subsequent identification of rational drug combinations to suppress resistance may greatly improve LGSOC treatment strategies. Both gain-of-function and loss-of-function CRISPR-Cas9 genome-wide libraries were used to screen LGSOC cell lines to identify genes that modulate the response to MEKi. Overexpression of MAML2 and loss of MAP3K1 were identified, both leading to overexpression of the NOT2022-01-01T00:00:00Z2022 Dec2026-05-28T03:50:36.993Z2025-04-06T14:11:36.433ZS-EPMC97162503619803110.1158/1535-7163.MCT-22-0004