title: PAK1 mediates resistance to PI3K inhibition in lymphomas.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  Thus, we show that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.
authors.affiliation: Duke Institute for Genome Sciences and Policy and Department of Medicine, Duke Cancer Institute, Duke University Medical Center, Duke University, Durham, North Carolina, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Walsh
authors.forename: Matthew S
authors.initials: MS
authors.lastname: McKinney
authors.forename: Cassandra
authors.initials: C
authors.lastname: Love
authors.forename: Qingquan
authors.initials: Q
authors.lastname: Liu
authors.forename: Alice
authors.initials: A
authors.lastname: Fan
authors.forename: Amee
authors.initials: A
authors.lastname: Patel
authors.forename: Jason
authors.initials: J
authors.lastname: Smith
authors.forename: Anne
authors.initials: A
authors.lastname: Beaven
authors.forename: Dereje D
authors.initials: DD
authors.lastname: Jima
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D014408:Biomarkers, Tumor / Q000235:genetics*; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D054852:Small Molecule Libraries; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014407:Tumor Cells, Cultured; D054462:p21-Activated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D014408:Biomarkers, Tumor; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054852:Small Molecule Libraries; D058570:TOR Serine-Threonine Kinases; D054462:p21-Activated Kinases; C570852:8-(6-methoxypyridin-3-yl)-3-methyl-1-(4-piperazin-1-yl-3-trifluoromethylphenyl)-1,3-dihydroimidazo(4,5-c)quinolin-2-one; C571178:NVP-BKM120; C546842:MTOR protein, human; C515903:PAK1 protein, human; C531198:dactolisib