RNA-interference or small molecule inhibition restore sensitivity to PI3 kinase inhibition. Scientific Category: Cancer Therapy: Preclinical Running Title: PI3K inhibition in lymphoma

Translational Relevance: Lymphomas are a common group of malignancies with a high degree of clinical and molecular heterogeneity. This poses a major problem in the effective identification of new therapies and in the design of new clinical trials. Current approaches to preclinical testing frequently rely on small numbers of lymphoma cell lines from individual histologies to identify new potential therapeutic targets for lymphomas. In this paper, we develop a different paradigm by testing three different drugs that target the PI3 kinase pathway in 60 different cell lines in conjunction with gene expression profiling. We found a significant heterogeneity in response to the drugs that was not related to histology. Through the examination of gene expression profiles, we identified PAK1 as a major mediator of resistance to PI3 kinase inhibition. We experimentally demonstrate that inhibition of PAK1 through either RNA-interference or small molecule inhibition restore sensitivity to PI3 kinase inhibition. Scientific Category: Cancer Therapy: Preclinical