Narrow-spectrum kinase inhibition has less proapoptotic activity than BEZ235. (A) A representative Eμ-Myc lymphoma (#4242) was treated in vitro for 48 hours with increasing concentrations of BEZ235 or a panel of more selective kinase inhibitors (BKM120, KU63794, KU59933, or KU57788) prior to flow cytometric analysis for annexin-V/PI positivity. (B) Eμ-Myc lymphoma derived on a LoxP-Rictor-LoxP background was transduced with MSCV-Cre recombinase (Cre) or empty vector (MSCV). Protein lysates were then separated by SDS-PAGE prior to immunoblotting for Rictor or Raptor expression. (C) Matched Rictor expressing (MSCV) and Rictor knockout (Cre) lymphomas were treated for 24 hours with BEZ235 or Everolimus prior to flow cytometric analysis for annexin-V/PI positivity. (D) Eμ-Myc lymphoma cells were treated with increasing concentrations of ATM inhibitor (KU55933), DNA-PK inhibitor (KU57788), or combined KU55933 and KU57788 alone or in combination with a fixed dose of Everolimus (100 nM) for 24 hours prior to flow cytometric analysis for annexin-V/PI staining. # indicates greater-than-additive apoptotic effect (SQ > 1) for the two-drug combination. All results are represented as the mean (± SEM) of at least 3 independent experiments.