PAK1 mediates resistance to PI3K inhibition in lymphomas

Clin Cancer Res. 2013 Mar 1;19(5):1106-15. doi: 10.1158/1078-0432.CCR-12-1060. Epub 2013 Jan 8.

Abstract

Purpose: The phosphoinositide 3-kinase (PI3K) pathway is known to play an active role in many malignancies. The role of PI3K inhibition in the treatment of lymphomas has not been fully delineated. We sought to identify a role for therapeutic PI3K inhibition across a range of B-cell lymphomas.

Experimental design: We selected three small molecule inhibitors to test in a panel of 60 cell lines that comprised diverse lymphoma types. We tested the selective PI3K inhibitor BKM120 and the dual PI3K/mTOR inhibitors BEZ235 and BGT226 in these cell lines. We applied gene expression profiling to better understand the molecular mechanisms associated with responsiveness to these drugs.

Results: We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference-mediated knockdown of the PAK1 gene, we showed a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small-molecule inhibitor of PAK1 and found significant synergy between PI3K and PAK1 inhibition.

Conclusion: Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminopyridines / pharmacology
  • Biomarkers, Tumor / genetics*
  • Cell Proliferation / drug effects
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Synergism
  • Enzyme Inhibitors / pharmacology*
  • Gene Expression Profiling
  • Humans
  • Imidazoles / pharmacology
  • Lymphoma / drug therapy*
  • Lymphoma / genetics
  • Lymphoma / metabolism
  • Morpholines / pharmacology
  • Oligonucleotide Array Sequence Analysis
  • Phosphatidylinositol 3-Kinases / metabolism
  • Phosphoinositide-3 Kinase Inhibitors*
  • Quinolines / pharmacology
  • RNA, Messenger / genetics
  • RNA, Small Interfering / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Small Molecule Libraries
  • TOR Serine-Threonine Kinases / antagonists & inhibitors*
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Cells, Cultured
  • p21-Activated Kinases / antagonists & inhibitors
  • p21-Activated Kinases / genetics
  • p21-Activated Kinases / metabolism*

Substances

  • 8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one
  • Aminopyridines
  • Biomarkers, Tumor
  • Enzyme Inhibitors
  • Imidazoles
  • Morpholines
  • NVP-BKM120
  • Phosphoinositide-3 Kinase Inhibitors
  • Quinolines
  • RNA, Messenger
  • RNA, Small Interfering
  • Small Molecule Libraries
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • PAK1 protein, human
  • p21-Activated Kinases
  • dactolisib