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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]

PMID: 23300274

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Project description:BACKGROUND:The phosphoinositol 3-kinase (PI3K) pathway is associated with poor prognosis of hematologic malignancies, providing a strong rationale for the use of PI3K inhibitors in the treatment of malignant lymphoma. However, development of resistance limits the use of PI3K inhibitors in lymphoma patients. METHODS:We established copanlisib (pan-PI3K inhibitor)-resistant B-cell lymphoma and duvelisib (PI3Kδ and -γ inhibitor)-resistant T-cell lymphoma cell lines. The cytokine array and the phospho-kinase array were used to identify up-regulated proteins in the resistant cells. Cytokine expression and phospho-kinase levels were examined by ELISA and Western blot analysis, respectively. Cell proliferation capabilities were measured by using CCK-8 kit and colony formation assay. The effects of inhibitors on apoptosis were detected using an Annexin V-FITC Apoptosis Detection Kit and a flow cytometry system. The underlying mechanisms were studied by transfecting recombinant plasmids or siRNA into lymphoma cell lines. Cells were transiently transfected using the Amaxa electroporation system. We evaluated the effects of PI3K inhibitor alone and in combination with JAK inhibitor (BSK805) on lymphoma proliferation and signaling pathway activation. RESULTS:Cytokine arrays revealed upregulation of interleukin (IL)-6 in both copanlisib- and duvelisib-resistant cell lines. Phosphorylated STAT5, AKT, p70S6K and MAPK were increased in copanlisib-resistant B-cell lymphoma cells, whereas phosphorylated STAT3 and NF-κB were increased in duvelisib-resistant T cell lymphoma cells. Conversely, depletion of IL-6 sensitized both resistant cell lines, and led to downregulation of phosphorylated STAT3 and STAT5 in copanlisib- and duvelisib-resistant cells, respectively. Moreover, combined treatment with a JAK inhibitor (BSK805) and a PI3K inhibitor circumvented the acquired resistance to PI3K inhibitors in lymphoma, and concurrent inhibition of the activated pathways produced combined effects. CONCLUSIONS:IL-6-induced STAT3 or STAT5 activation is a critical mechanism underlying PI3K inhibitor resistance in lymphoma, supporting the utility of IL-6 as an effective biomarker to predict therapeutic response to PI3K inhibitors.

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PAK1 mediates resistance to PI3K inhibition in lymphomas.

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PAK1 mediates resistance to PI3K inhibition in lymphomas.

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