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

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

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)81794-81802
Number of pages9
JournalOncotarget
Volume8
Issue number47
DOIs
StatePublished - 2017

Bibliographical note

Publisher Copyright:
© Pongas et al.

Keywords

  • ABC DLBCL
  • BYL719
  • DLBCL
  • Idelalisib
  • PI3K

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