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Ann Oncol. 2016 Jun;27(6):1123-8. doi: 10.1093/annonc/mdw131. Epub 2016 Mar 8.

Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas.

Author information

1
Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
2
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.
3
Unit of Lymphoid Malignancies, Department of Onco-Haematology, San Raffaele Scientific Institute, Milan, Italy.
4
Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
5
IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
6
Translational and Biomarker Research, Translational Innovation Platform Oncology, EMD Serono Research and Development Institute, Billerica, USA.
7
Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland frbertoni@mac.com.

Abstract

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.

KEYWORDS:

diffuse large B-cell lymphoma; ibrutinib; idelalisib; mantle cell lymphoma

PMID:
26961147
DOI:
10.1093/annonc/mdw131
[Indexed for MEDLINE]

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