Abstract 2673: Idelalisib has activity at clinically achievable drug concentrations in a subset of ABC and GCB diffuse large B-cell lymphoma and transformed follicular lymphoma cell lines
Authors: Jia Y. Liu, Tom Kenney, Leslie Butterworth, Adam Kashishian, Sarah Meadows, Peng Yue, Li Li, Kathleen Keegan, Christophe Quéva, Stacey Tannheimer
Journal: Cancer Research (2015)

Abstract Diffuse large B-cell lymphoma (DLBCL) is the largest lymphoma subtype representing approximately one-third of all cases of non-Hodgkin's lymphoma. Gene expression profiling showed that DLBCL can be stratified into activated B-cell (ABC) or germinal center B-cell (GCB) subtypes (Alizadeh et al., Nature 2000). The overall five year survival rate is only approximately 50% (Shaffer et al., Annu. Rev. Immunol. 2012), thus a medical need exits for the treatment of this disease, particularly for patients who relapse after the first line chemoimmunotherapy regimen. Idelalisib is an investigational, highly selective oral inhibitor of phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) delta isoform. PI3K delta signaling is required for B lymphocyte activation, proliferation and survival and is dysregulated in several B-cell malignancies. We investigated the activity of idelalisib and ibrutinib, an inhibitor of Bruton's tyrosine kinase, on the inhibition of proliferation against a panel of 22 DLBCL (9 ABC, 13 GCB) and 3 transformed follicular lymphoma cell lines. Idelalisib has potent activity (EC50&amp;lt;300nM) against 3 of 9 (33%) ABC, 3 of 13 (23%) GCB DLBCL and 1 of 3 (33%) transformed follicular lymphoma cell lines at clinically achievable concentrations (culture media protein binding adjusted Cmax 421nM). In contrast, ibrutinib has activity (EC50&amp;lt;40nM) against only 3 of 9 (33%) ABC DLBCL cell lines at clinically achievable concentrations (culture media protein binding adjusted Cmax 48nM). Interestingly, the same three ABC DLBCL cells lines are sensitive to both idelalisib and ibrutinib. Although all of the B-lymphoma cell lines express multiple PI3K isoforms, the PI3K delta isoform is the most highly expressed across all malignant B lymphoma cell lines evaluated. We show that PI3K delta is essential for proliferation in the idelalisib sensitive cell lines using PI3K alpha, beta, or delta isoform selective inhibitors. Further, we demonstrate that idelalisib blocks AKT and RPS6 phosphorylation. Activating mutations in CD79 subunits of the B-cell receptor are associated with sensitivity to idelalisib and ibrutinib in ABC DLBCL cell lines. The absence of PTEN protein in GCB DLBCL cell lines does not correlate with increased sensitivity to idelalisib. Baseline and drug treatment gene expression analysis to investigate differential pathways driving growth and survival in responding versus non responding cell types has been performed and results will be presented. These data support advancing idelalisib in clinical trials for the treatment of a select subgroup of DLBCL patient population Citation Format: Jia Y. Liu, Tom Kenney, Leslie Butterworth, Adam Kashishian, Sarah Meadows, Peng Yue, Li Li, Kathleen Keegan, Christophe Quéva, Stacey Tannheimer. Idelalisib has activity at clinically achievable drug concentrations in a subset of ABC and GCB diffuse large B-cell lymphoma and transformed follicular lymphoma cell lines. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2673. doi:10.1158/1538-7445.AM2015-2673