Concurrent MEK targeted therapy prevents MAPK pathway reactivation during BRAFV600E targeted inhibition in a novel syngeneic murine glioma model
| Autor: | David James, Nathalene Truffaux, Albert Truong, Ian Meyers, Stefan Grossauer, Mitchel S. Berger, Nicole E. Murphy, Martin McMahon, Katharina Koeck, Joanna J. Phillips, Theodore Nicolaides, Mathieu Daynac, Claudia Petritsch |
|---|---|
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
MAPK/ERK pathway Gene Expression Apoptosis Mice Gene Knockout Techniques syngeneic high-grade astrocytoma model 0302 clinical medicine Molecular Targeted Therapy Isogeneic Cancer Trametinib Tumor Kinase Brain Neoplasms MEK inhibitor Melanoma Glioma 3. Good health Oncology 5.1 Pharmaceuticals 030220 oncology & carcinogenesis medicine.drug Research Paper Biotechnology Proto-Oncogene Proteins B-raf Genotype MAP Kinase Signaling System Oncology and Carcinogenesis Antineoplastic Agents Cell Line 03 medical and health sciences Rare Diseases Cell Line Tumor primary adaptive therapy resistance medicine Animals Humans dabrafenib Codon MAPK pathway reactivation Protein kinase B Protein Kinase Inhibitors Cell Proliferation Transplantation business.industry Animal Neurosciences Dabrafenib medicine.disease Brain Disorders Enzyme Activation Brain Cancer Disease Models Animal Transplantation Isogeneic 030104 developmental biology Immunology Disease Models Mutation Cancer research Neoplasm Grading business |
| Zdroj: | Oncotarget, vol 7, iss 46 Oncotarget |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|