title: Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model.
abstract: Inhibitors of BRAFV600E kinase are currently under investigations in preclinical and clinical studies involving BRAFV600E glioma. Studies demonstrated clinical response to such individualized therapy in the majority of patients whereas in some patients tumors continue to grow despite treatment. To study resistance mechanisms, which include feedback activation of mitogen-activated protein kinase (MAPK) signaling in melanoma, we developed a luciferase-modified cell line (2341luc) from a BrafV600E mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAFV600E- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341luc were tested for effects of BRAFV600E and MEK inhibitor treatments, with bioluminescence imaging up to 14-days after start of treatment and survival analysis as primary indicators of inhibitor activity. Intracranial injected tumor cells consistently generated high-grade glioma-like tumors in syngeneic mice. Intraperitoneal daily delivery of BRAFV600E inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341luc tumor. MEK inhibitor trametinib delivered by oral gavage daily suppressed MAPK pathway more effectively and had a more durable anti-growth effect than dabrafenib as well as a significant survival benefit. Compared with either agent alone, combined BRAFV600E and MEK inhibitor treatment was more effective in reducing tumor growth and extending animal subject survival, as corresponding to sustained MAPK pathway inhibition. Results derived from the 2341luc engraftment model application have clinical implications for the management of BRAFV600E glioma.
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Grossauer
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Katharina
authors.initials: K
authors.lastname: Koeck
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Murphy
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Ian D
authors.initials: ID
authors.lastname: Meyers
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Daynac
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Nathalene
authors.initials: N
authors.lastname: Truffaux
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.|Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Truong
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.|Department of Pediatrics, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Nicolaides
authors.affiliation: Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: McMahon
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Mitchel S
authors.initials: MS
authors.lastname: Berger
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.
authors.forename: Joanna J
authors.initials: JJ
authors.lastname: Phillips
authors.affiliation: Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: C David
authors.initials: CD
authors.lastname: James
authors.affiliation: Department of Neurological Surgery, Brain Tumor Research Center, San Francisco, CA 94158, USA.|Helen Diller Comprehensive Cancer Research Center, University of California San Francisco, San Francisco, CA 94158, USA.|Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, University of California San Francisco, San Francisco, CA 94158, USA.
authors.forename: Claudia K
authors.initials: CK
authors.lastname: Petritsch
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003062:Codon; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D015870:Gene Expression; D055786:Gene Knockout Techniques; D005838:Genotype; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D058990:Molecular Targeted Therapy; D009154:Mutation; D060787:Neoplasm Grading; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics*; D014185:Transplantation, Isogeneic
chemical_list: D000970:Antineoplastic Agents; D003062:Codon; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf
keywords: MAPK pathway reactivation; dabrafenib; primary adaptive therapy resistance; syngeneic high-grade astrocytoma model