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PI3K? inhibition causes feedback activation of PI3K? in the ABC subtype of diffuse large B-cell lymphoma.

ABSTRACT: Cell line models of the activated B cell-like (ABC) subtype of diffuse large B cell (DLBCL) depend on both NF-?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? isoform, but that PI3K pathway interruption by PI3K? inhibitors is short-lived due to feedback activation of the PI3K? isoform. PI3K? and PI3K? inhibition cooperated in killing ABC DLBCL lines, and genetic knockdown of PI3K? sensitized cells to PI3K? inhibition and prolonged the interruption of PI3K signaling. PI3K? inhibition evoked feedback activation of proximal BCR signaling, which increased the association of PI3K? with BCAP and CD19 and increased overall PI3K activity. These results support the clinical evaluation of dual PI3K? and PI3K? inhibition in patients with ABC DLBCL.

SUBMITTER: Pongas GN

PROVIDER: S-EPMC5669848 | biostudies-other | 2017 Oct

REPOSITORIES: biostudies-other

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

Pongas Georgios N GN Annunziata Christina M CM Staudt Louis M LM

Oncotarget 20170913 47

Cell line models of the activated B cell-like (ABC) subtype of diffuse large B cell (DLBCL) depend on both NF-κB 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 PI3Kδ isoform, but that PI3K pathway interruption by PI3Kδ inhibitors is short-lived due to feedback activation of the PI3Kα isoform. PI3Kδ and PI3Kα inhibition cooperated in killing A ...[more]

PMID: 29137222

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