title: Combination of the MEK inhibitor pimasertib with BTK or PI3K-delta inhibitors is active in preclinical models of aggressive lymphomas.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  The data presented here provide the basis for further investigation of regimens including pimasertib in relapsed and refractory lymphomas.
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
authors.forename: E
authors.initials: E
authors.lastname: Gaudio
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
authors.forename: C
authors.initials: C
authors.lastname: Tarantelli
authors.affiliation: 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.
authors.forename: I
authors.initials: I
authors.lastname: Kwee
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
authors.forename: C
authors.initials: C
authors.lastname: Barassi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
authors.forename: E
authors.initials: E
authors.lastname: Bernasconi
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
authors.forename: A
authors.initials: A
authors.lastname: Rinaldi
authors.affiliation: Unit of Lymphoid Malignancies, Department of Onco-Haematology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona; IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: L
authors.initials: L
authors.lastname: Cascione
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona.
authors.forename: A
authors.initials: A
authors.lastname: Targa
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Stathis
authors.affiliation: Translational and Biomarker Research, Translational Innovation Platform Oncology, EMD Serono Research and Development Institute, Billerica, USA.
authors.forename: S
authors.initials: S
authors.lastname: Goodstal
authors.affiliation: IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Zucca
authors.affiliation: Lymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona; IOSI Oncology Institute of Southern Switzerland, Bellinzona, Switzerland. Electronic address: frbertoni@mac.com.
authors.forename: F
authors.initials: F
authors.lastname: Bertoni
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives; D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D045744:Cell Line, Tumor; D058534:Class I Phosphatidylinositol 3-Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D016393:Lymphoma, B-Cell / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics; D051379:Mice; D058990:Molecular Targeted Therapy; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D010880:Piperidines; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics*; D011687:Purines / Q000008:administration & dosage; D011720:Pyrazoles / Q000008:administration & dosage; D011743:Pyrimidines / Q000008:administration & dosage; D052999:Quinazolinones / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C550600:N-(2,3-dihydroxypropyl)-1-((2-fluoro-4-iodophenyl)amino)isonicotinamide; D010880:Piperidines; D011687:Purines; D011720:Pyrazoles; D011743:Pyrimidines; D052999:Quinazolinones; C551803:ibrutinib; D009536:Niacinamide; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; D020930:MAP Kinase Kinase Kinases; D000225:Adenine; C552946:idelalisib
keywords: diffuse large B-cell lymphoma; ibrutinib; idelalisib; mantle cell lymphoma