Taselisib ( XXXX ), a Potent b-Sparing Small Molecule Inhibitor of @entity3115 , Radiosensitizes Head and Neck Squamous Carcinomas Containing Activating @entity20721 Alterations.

@entity3115 @entity137 @entity20721 @entity19 @entity72265 @entity16 @entity2370 @entity10440 @entity213
PURPOSE: Activating @entity20721 genomic alterations are frequent in @entity213 ( @entity213 ), and there is an association between @entity3115 ( @entity3115 ) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting @entity3115 with @entity72265 , a @entity3115 inhibitor with potent activity against @entity20721 , in combination with radiation in @entity213 . EXPERIMENTAL DESIGN: The efficacy of @entity72265 was assessed in vitro in 26 @entity213 cell lines with crystal violet proliferation assays, and changes in @entity3115 signaling were measured by Western blot analysis. @entity137 and radiosensitization were assessed with @entity10440 staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for yH2AX foci, and cell cycle analysis was performed with flow cytometry. In vivo efficacy of @entity72265 and radiation was assessed in xenografts implanted into @entity19 . RESULTS: @entity72265 inhibited potently @entity3115 signaling and displayed greater antiproliferative activity in @entity213 cell lines with @entity20721 mutations or amplification, whereas cell lines with @entity2370 alterations were relatively resistant to its effects. Pretreatment with @entity72265 radiosensitized @entity20721 -mutant @entity213 cells, enhanced radiation-induced apoptosis, @entity16 repair, and prolonged G2-M arrest following irradiation. Furthermore, combined @entity72265 and radiation was more effective than either treatment alone in vivo in subcutaneous xenograft models. CONCLUSIONS: @entity72265 has increased potency in @entity213 cell lines harboring @entity20721 -activating aberrations. Further, combined @entity72265 and radiotherapy was more efficacious than either treatment alone in @entity20721 -altered @entity213 in vitro and in vivo. This strategy warrants further clinical investigation. Clin Cancer Res; 1-11.   2015 AACR.
