Journal article
Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas.
- Gaudio E Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
- Tarantelli C Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
- Kwee I Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona; Dalle Molle Institute for Artificial Intelligence (IDSIA), Manno; Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland.
- Barassi C Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
- Bernasconi E Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
- Rinaldi A Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
- Ponzoni M Unit of Lymphoid Malignancies, Department of Onco-Haematology, San Raffaele Scientific Institute, Milan, Italy.
- Cascione L Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona; IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Targa A Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
- Stathis A IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Goodstal S Translational and Biomarker Research, Translational Innovation Platform Oncology, EMD Serono Research and Development Institute, Billerica, USA.
- Zucca E IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
- Bertoni F Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona; IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. Electronic address: frbertoni@mac.com.
- 2016-03-11
Published in:
- Annals of oncology : official journal of the European Society for Medical Oncology. - 2016
diffuse large B-cell lymphoma
ibrutinib
idelalisib
mantle cell lymphoma
Agammaglobulinaemia Tyrosine Kinase
Animals
Cell Line, Tumor
Class I Phosphatidylinositol 3-Kinases
Drug Synergism
Gene Expression Regulation, Neoplastic
Humans
Lymphoma, B-Cell
MAP Kinase Kinase Kinases
Mice
Molecular Targeted Therapy
Niacinamide
Protein-Tyrosine Kinases
Purines
Pyrazoles
Pyrimidines
Quinazolinones
Signal Transduction
Xenograft Model Antitumor Assays
English
BACKGROUND
Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models.
MATERIALS AND METHODS
Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed.
RESULTS
Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib.
CONCLUSION
The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.
Lymphomas are among the most common human cancers and represent the cause of death for still too many patients. The B-cell receptor with its downstream signaling pathways represents an important therapeutic target for B-cell lymphomas. Here, we evaluated the activity of the MEK1/2 inhibitor pimasertib as single agent and in combination with other targeted drugs in lymphoma preclinical models.
MATERIALS AND METHODS
Cell lines derived mature B-cell lymphomas were exposed to increasing doses of pimasertib alone. Immunoblotting and gene expression profiling were performed. Combination of pimasertib with idelalisib or ibrutinib was assessed.
RESULTS
Pimasertib as single agent exerted a dose-dependent antitumor activity across a panel of 23 lymphoma cell lines, although at concentrations higher than reported for solid tumors. Strong synergism was observed with pimasertib combined with the PI3K inhibitor idelalisib and the BTK inhibitor ibrutinib in cell lines derived from diffuse large B-cell lymphoma (DLBCL) and mantle cell lymphoma. The data were confirmed in an in vivo experiment treating DLBCL xenografts with pimasertib and ibrutinib.
CONCLUSION
The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.
- Language
-
- English
- Open access status
- bronze
- Identifiers
-
- DOI 10.1093/annonc/mdw131
- PMID 26961147
- Persistent URL
- https://sonar.ch/global/documents/146061
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