Vertical Inhibition of the RAF-MEK-ERK Cascade Induces Myogenic Differentiation, Apoptosis, and Tumor Regression in H/NRAS Q61X Mutant Rhabdomyosarcoma.

Autor:	Garcia N; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas., Del Pozo V; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas., Yohe ME; Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Goodwin CM; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina., Shackleford TJ; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas.; St. Mary's University, San Antonio Texas., Wang L; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas., Baxi K; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas., Chen Y; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.; Department of Population Health Sciences, The University of Texas Health Science Center, San Antonio, Texas., Rogojina AT; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas., Zimmerman SM; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Peer CJ; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Figg WD; Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland., Ignatius MS; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas., Wood KC; Department of Pharmacology and Cancer Biology, Duke University, Durham, North Carolina., Houghton PJ; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas.; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas., Vaseva AV; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center, San Antonio, Texas. vaseva@uthscsa.edu.; Department of Molecular Medicine, The University of Texas Health Science Center, San Antonio, Texas.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2022 Jan; Vol. 21 (1), pp. 170-183. Date of Electronic Publication: 2021 Nov 04.
DOI:	10.1158/1535-7163.MCT-21-0194
Abstrakt:	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 H/NRAS Q61X mutant RMS cells and correlates in vivo 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 H/NRAS Q61X dependency in RMS cells; however, there is poor in vivo 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. In vivo assessment of pan-RAFi + ERKi or MEKi + ERKi potently suppress growth of H/NRAS Q61X 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 H/NRAS Q61X mutant RMS tumor growth. (©2021 American Association for Cancer Research.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu