Oncotarget

Priority Research Papers:

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

Georgios N. Pongas, Christina M. Annunziata and Louis M. Staudt _

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Oncotarget. 2017; 8:81794-81802. https://doi.org/10.18632/oncotarget.20864

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Abstract

Georgios N. Pongas1,2,3, Christina M. Annunziata2,3 and Louis M. Staudt1

1 Lymphoid Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

2 Medical Oncology Service, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

3 Women’s Malignancies Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA

Correspondence to:

Louis M. Staudt, email:

Keywords: DLBCL, PI3K, Idelalisib, ABC DLBCL, BYL719

Received: August 07, 2017 Accepted: August 15, 2017 Published: September 13, 2017

Abstract

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 ABC DLBCL lines, and genetic knockdown of PI3Kα sensitized cells to PI3Kδ inhibition and prolonged the interruption of PI3K signaling. PI3Kδ inhibition evoked feedback activation of proximal BCR signaling, which increased the association of PI3Kα with BCAP and CD19 and increased overall PI3K activity. These results support the clinical evaluation of dual PI3Kδ and PI3Kα inhibition in patients with ABC DLBCL.


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