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• W4362511933 abstract "<div>Abstract<p>Oncogenic RAS signaling is an attractive target for fusion-negative rhabdomyosarcoma (FN-RMS). Our study validates the role of the ERK MAPK effector pathway in mediating RAS dependency in a panel of <i>H/NRAS^Q61X</i> mutant RMS cells and correlates <i>in vivo</i> efficacy of the MEK inhibitor trametinib with pharmacodynamics of ERK activity. A screen is used to identify trametinib-sensitizing targets, and combinations are evaluated in cells and tumor xenografts. We find that the ERK MAPK pathway is central to <i>H/NRAS^Q61X</i> dependency in RMS cells; however, there is poor <i>in vivo</i> response to clinically relevant exposures with trametinib, which correlates with inefficient suppression of ERK activity. CRISPR screening points to vertical inhibition of the RAF–MEK–ERK cascade by cosuppression of MEK and either CRAF or ERK. CRAF is central to rebound pathway activation following MEK or ERK inhibition. Concurrent CRAF suppression and MEK or ERK inhibition, or concurrent pan-RAF and MEK/ERK inhibition (pan-RAFi + MEKi/ERKi), or concurrent MEK and ERK inhibition (MEKi + ERKi) all synergistically block ERK activity and induce myogenic differentiation and apoptosis. <i>In vivo</i> assessment of pan-RAFi + ERKi or MEKi + ERKi potently suppress growth of <i>H/NRAS^Q61X</i> RMS tumor xenografts, with pan-RAFi + ERKi being more effective and better tolerated. We conclude that CRAF reactivation limits the activity of single-agent MEK/ERK inhibitors in FN-RMS. Vertical targeting of the RAF–MEK–ERK cascade and particularly cotargeting of CRAF and MEK or ERK, or the combination of pan-RAF inhibitors with MEK or ERK inhibitors, have synergistic activity and potently suppress <i>H/NRAS^Q61X</i> mutant RMS tumor growth.</p></div>" @default.
• W4362511933 created "2023-04-06" @default.
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• W4362511933 date "2023-04-03" @default.
• W4362511933 modified "2023-10-16" @default.
• W4362511933 title "Data from Vertical Inhibition of the RAF–MEK–ERK Cascade Induces Myogenic Differentiation, Apoptosis, and Tumor Regression in <i>H/NRAS^Q61X</i> Mutant Rhabdomyosarcoma" @default.
• W4362511933 doi "https://doi.org/10.1158/1535-7163.c.6543340.v1" @default.
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