期刊
ONCOTARGET
卷 7, 期 46, 页码 75839-75853出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12419
关键词
MAPK pathway reactivation; dabrafenib; primary adaptive therapy resistance; syngeneic high-grade astrocytoma model
资金
- National Institute of Health/National Cancer Institute [CA16476-04]
- National Institute of Neurological Disorders and Stroke [NS080619]
- Childhood Brain Tumor Foundation
- Loglio Research Program
- Research Allocation Program Investigator Grant CTSI-UCSF
- California Institute of Regenerative Medicine [TB1-01190]
Inhibitors of BRAF(V600E) kinase are currently under investigations in preclinical and clinical studies involving BRAF(V600E) 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 (2341(luc)) from a BRAF(V600E) mutant and Cdkn2a- deficient murine high-grade glioma, and analyzed its molecular responses to BRAF(V600E)- and MAPK kinase (MEK)-targeted inhibition. Immunocompetent, syngeneic FVB/N mice with intracranial grafts of 2341(luc) were tested for effects of BRAF(V600E) 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 BRAF(V600E) inhibitor dabrafenib only transiently suppressed MAPK signaling, and rather increased Akt signaling and failed to extend survival for mice with intracranial 2341(luc) 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 BRAF(V600E) 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 2341(luc) engraftment model application have clinical implications for the management of BRAF(V600E) glioma.
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