Simultaneous Inhibition of PI3Kδ and PI3Kα Induces ABC-DLBCL Regression by Blocking BCR-Dependent and -Independent Activation of NF-κB and AKT

Cancer Cell. 2017 Jan 9;31(1):64-78. doi: 10.1016/j.ccell.2016.12.003.

Abstract

Compared with follicular lymphoma, high PI3Kα expression was more prevalent in diffuse large B cell lymphoma (DLBCL), although both tumor types expressed substantial PI3Kδ. Simultaneous inhibition of PI3Kα and PI3Kδ dramatically enhanced the anti-tumor profile in ABC-DLBCL models compared with selective inhibition of PI3Kδ, PI3Kα, or BTK. The anti-tumor activity was associated with suppression of p-AKT and a mechanism of blocking nuclear factor-κB activation driven by CD79mut, CARD11mut, TNFAIP3mut, or MYD88mut. Inhibition of PI3Kα/δ resulted in tumor regression in an ibrutinib-resistant CD79BWT/MYD88mut patient-derived ABC-DLBCL model. Furthermore, rebound activation of BTK and AKT was identified as a mechanism limiting CD79Bmut-ABC-DLBCL to show a robust response to PI3K and BTK inhibitor monotherapies. A combination of ibrutinib with the PI3Kα/δ inhibitor copanlisib produced a sustained complete response in vivo in CD79Bmut/MYD88mut ABC-DLBCL models.

Keywords: BCR; CARD11; DLBCL; MYD88; NF-κB; PI3Kα; PI3Kδ; copanlisib; follicular lymphoma; ibrutinib-resistance.

MeSH terms

  • Adult
  • Agammaglobulinaemia Tyrosine Kinase
  • Aged
  • Animals
  • Cell Line, Tumor
  • Class I Phosphatidylinositol 3-Kinases / antagonists & inhibitors*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Lymphoma, Large B-Cell, Diffuse / drug therapy*
  • Lymphoma, Large B-Cell, Diffuse / mortality
  • Lymphoma, Large B-Cell, Diffuse / pathology
  • Mice
  • Mice, Inbred BALB C
  • Middle Aged
  • NF-kappa B / physiology*
  • Phosphoinositide-3 Kinase Inhibitors*
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Proto-Oncogene Proteins c-akt / physiology*
  • Pyrazoles / pharmacology
  • Pyrimidines / pharmacology
  • Quinazolines / pharmacology
  • Receptors, Antigen, B-Cell / physiology*

Substances

  • NF-kappa B
  • Phosphoinositide-3 Kinase Inhibitors
  • Pyrazoles
  • Pyrimidines
  • Quinazolines
  • Receptors, Antigen, B-Cell
  • ibrutinib
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PIK3CD protein, human
  • Protein-Tyrosine Kinases
  • Agammaglobulinaemia Tyrosine Kinase
  • BTK protein, human
  • Proto-Oncogene Proteins c-akt
  • Extracellular Signal-Regulated MAP Kinases
  • copanlisib