PAK1 Mediates Resistance to PI3 Kinase Inhibition in Lymphomas
Menée sur des lignées cellulaires de lymphomes, cette étude identifie le rôle joué par le gène PAK1 dans l'apparition d'une résistance à un traitement par inhibiteur de la signalisation PI3K
Purpose: 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. Results: 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. Conclusion: Thus we demonstrate that PI3K inhibition is broadly effective in lymphomas and PAK1 is a key modulator of resistance to PI3K inhibition.