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1.  PAK1 Mediates Resistance to PI3 Kinase Inhibition in Lymphomas 
The phosphatidylinositol 3-kinase pathway (PI3K) 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.
We found that higher expression of the PAK1 gene was significantly associated with resistance to all three PI3K inhibitors. Through RNA-interference mediated knock-down of the PAK1 gene, we demonstrated a dramatic increase in the sensitivity to PI3K inhibition. We further tested a small molecule inhibitor of PAK1 and found significant synergy between PI3K inhibition and PAK1 inhibition.
Thus we demonstrate that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.
PMCID: PMC3594365  PMID: 23300274
Leukemias and lymphomas; kinase and phosphatase inhibitors; diffuse large B cell lymphoma; DLBCL; Hodgkin lymphoma; Burkitt lymphoma; primary mediastinal B cell lymphoma; phosphatidylinositol 3-kinase pathway; PI3 Kinase; PI3K; PAK1; drug resistance
3.  Enhanced transcription of complement and coagulation genes in the absence of adaptive immunity 
Molecular immunology  2009;46(7):1505-1516.
A recessive nonsense mutation in the zebrafish recombination activating gene 1 (rag1) gene results in defective V(D)J recombination; however, animals homozygous for this mutation (rag1-/-) are reportedly viable and fertile in standard, nonsterile aquarium conditions but display increased mortality after intraperitoneal injection with mycobacteria. Based on their survival in nonsterile environments, we hypothesized that the rag1-/- zebrafish may possess an “enhanced” innate immune response to compensate for the lack of an adaptive immune system. To test this hypothesis, microarray analyses were used to compare the expression profiles of the intestines and hematopoietic kidneys of rag1 deficient zebrafish to the expression profiles of control (heterozygous) siblings. The expression levels of 12 genes were significantly altered in the rag1-/- kidney including the up regulation of a putative interferon stimulated gene, and the down regulation of genes encoding fatty acid binding protein 10, keratin 5 and multiple heat shock proteins. The expression levels of 87 genes were shown to be significantly altered in the rag1-/- intestine; the majority of these differences reflect increased expression of innate immune genes, including those of the coagulation and complement pathways. Subsequent analyses of orthologous coagulation and complement genes in Rag1-/- mice indicate increased transcription of the complement C4 gene in the Rag1-/-intestine.
PMCID: PMC2735268  PMID: 19200601
zebrafish; mouse; rag1; innate immunity; SCID

Results 1-3 (3)