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PAK1 mediates resistance to PI3K inhibition in lymphomas.


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

SUBMITTER: Walsh K 

PROVIDER: S-EPMC3594365 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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PAK1 mediates resistance to PI3K inhibition in lymphomas.

Walsh Katherine K   McKinney Matthew S MS   Love Cassandra C   Liu Qingquan Q   Fan Alice A   Patel Amee A   Smith Jason J   Beaven Anne A   Jima Dereje D DD   Dave Sandeep S SS  

Clinical cancer research : an official journal of the American Association for Cancer Research 20130108 5


<h4>Purpose</h4>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.<h4>Experimental design</h4>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  ...[more]

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