Co-inhibition of BET proteins and PI3Kα triggers mitochondrial apoptosis in rhabdomyosarcoma cells

Remodeling transcription by targeting bromodomain and extraterminal (BET) proteins has emerged as promising anticancer strategy. Here, we identify a novel synergistic interaction of the BET inhibitor JQ1 with the PI3Kα-specific inhibitor BYL719 to trigger mitochondrial apoptosis and to suppress tumor growth in models of rhabdomyosarcoma (RMS). RNA-Seq revealed that JQ1/BYL719 co-treatment shifts the overall balance of BCL-2 family gene expression towards apoptosis and upregulates expression of BMF, BCL2L11 (BIM) and PMAIP1 (NOXA) while downregulating BCL2L1 (BCL-xL). RNA expression profiles were generated by RNA-seq in biological triplicates from Rh30 cells treated for 6h with either 1) solvent, 2) 1µM JQ1, 3) 3µM BYL719 or 4) 1µM JQ1 / 3µM BYL719 using HiSeq4000 (Illumina).