PI3Kδ inhibition causes feedback activation of PI3Kα in the ABC subtype of diffuse large B-cell lymphoma

Cell line models of the activated B cell-like (ABC) subtype of diffuse large B cell (DLBCL) depend on both NF-kappa B and phosphatidylinositol 3-kinase (PI3K) signaling pathways for survival, especially those with gain-of-function B cell receptor (BCR) mutations. Here we show that these cells depend specifically on the PI3K delta isoform, but that PI3K pathway interruption by PI3K delta inhibitors is short-lived due to feedback activation of the PI3K alpha isoform. PI3K delta and PI3K alpha inhibition cooperated in killing ABC DLBCL lines, and genetic knockdown of PI3K alpha sensitized cells to PI3K delta inhibition and prolonged the interruption of PI3K signaling. PI3K delta inhibition evoked feedback activation of proximal BCR signaling, which increased the association of PI3K alpha with BCAP and CD19 and increased overall PI3K activity. These results support the clinical evaluation of dual PI3K delta and PI3K alpha inhibition in patients with ABC DLBCL.