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• W1909968650 abstract "Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CATreatment of patients with lymphomas resistant/refractory to standard chemotherapy is challenging. Development and identification of new compounds targeting components of relevant pathways is needed. Pimasertib is a potent and highly selective ATP noncompetitive MEK1/2 inhibitor, which has been shown able to induce G1 cell cycle arrest and apoptosis in different pre-clinical cancer models and potent antitumor activity in xenograft models with mainly BRAF and KRAS activating mutations. Here, we report data on the evaluation of pimasertib in a large panel of B-cell lymphoma cell lines.Methods.Cell lines from diffuse large B-cell lymphoma (DLBCL, n=16), mantle cell lymphoma (MCL, n=4), splenic marginal zone lymphoma (SMZL, n=3) underwent 72 hrs exposure to increasing doses of pimasertib (EMD Merck KGaA, Darmstadt, Germany) to assess anti-proliferative activity by MTT assay. Apoptosis was assessed by Annexin-V/7-AAD staining, gene expression profiling (GEP) with Illumina HumanHT-12 Expression BeadChips at baseline on all the cell lines. GEP/IC50 correlation was assessed by Spearman correlation. Cell lines with IC50 < 15μM were defined as sensitive; data mining included LIMMA, GSEA and Metacore. Three DLBCL cell lines were exposed to increasing doses of pimasertib in combination with other drugs, and synergy was assessed by Chou-Talalay combination index (CI).Results. The median IC50 value was 26.1 μM (range, 1.4-100 μM). The effect was largely cytostatic, with apoptosis detected in 1/5 cell lines and only at high doses (80 μM). DLBCL and SMZL cells appeared more sensitive than MCL (P=0.047 and P=0.039). No differences were observed between germinal center B-cell or activated B-cell (ABC) DLBCL. TP53 (P=0.0283) and TNFAIP3 (P=0.012) inactivation negatively affected the response to pimasertib. Transcripts significantly associated with higher sensitivity to pimasertib were enriched of MEK and RAS regulated genes, E2F target genes, genes expressed in germinal center B cells. Transcripts associated with resistance were enriched of IFN target genes (including TNFAIP3) and genes down-regulated in the presence of active MEK or RAS.Pimasertib showed synergism combined with PI3K inhibitor idelalisib (median CI=0.34), and the effect was strong in 2/3 cell lines (OCI-Ly10, CI= 0.03; TMD8, CI= 0.25). Synergism was observed with BTK-inhibitor ibrutinib in the ABC-DLBCL cell lines (OCI-Ly10, CI=0.32; TMD8, CI=0.63). Less synergistic effects were observed with pimasertib in combination with anti-CD20 moAb rituximab (CI=0.78) and with MDM2 inhibitor nutlin-3 (CI=0.67).Conclusions. Pimasertib showed promising activity in combination with PI3K and BTK inhibitors in preclinical models of mature lymphomas, worth of being further evaluated. GEP signatures associated with the response to pimasertib were identified.Citation Format: Eugenio Gaudio, Ivo Kwee, Chiara Tarantelli, Elena Bernasconi, Andrea Rinaldi, Luciano Cascione, Maurilio Ponzoni, Anastasios Stathis, Emanuele Zucca, Samantha Goodstal, Francesco Bertoni. The MEK-inhibitor pimasertib in B-cell lymphomas: Evaluation of the pre-clinical activity as single agent or in combination and identification of biomarkers of response. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 739. doi:10.1158/1538-7445.AM2014-739" @default.
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• W1909968650 date "2014-09-30" @default.
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• W1909968650 title "Abstract 739: The MEK-inhibitor pimasertib in B-cell lymphomas: Evaluation of the pre-clinical activity as single agent or in combination and identification of biomarkers of response" @default.
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