PI3K Inhibitors Inhibit Lymphoma Growth by Downregulation of MYC-Dependent Proliferation.
Poster Board I-723
The phosphatidylinositol 3'-kinase (PI3K) signaling pathway is known to play an important role in proliferation in B cell lymphomas, as well as a variety of malignancies. The role of PI3K-inhibition as a therapeutic option in lymphomas has not been fully explored. Rad001, BEZ235, and BKM120 are novel small molecule inhibitors that inhibit the PI3K pathway. RAD001 selectively inhibits the mTOR pathway, which is directly downstream of the PI3K pathway in B cell lymphomas. BEZ235 is a dual inhibitor of the mTOR and PI3K pathways, and BKM120 selectively inhibits the PI3K pathway. We sought to identify a role for PI3K inhibition in the treatment of lymphomas.
Methods and Results
We obtained specific small molecule PI3K inhibitors RAD001, BEZ235, and BKM120 and tested them in preclinical models of lymphoma. These drugs were tested in 18 cell lines that comprise 5 different lymphoid malignancies: Burkitt's lymphoma, mantle cell lymphoma, Hodgkin's lymphoma, multiple myeloma and diffuse large B cell lymphoma. Each drug was tested separately in these cell lines and was found to be lethal at IC50 concentrations varying from 46 nM to 28 microM, suggesting that the drugs could be effective in treating lymphomas at physiologically achievable concentrations.
In order to better understand the downstream effects of PI3K inhibition, we performed time course experiments on cell lines post-treatment with each of the drugs. At time points 6, 12, and 24 hours, we obtained lymphoma cells treated with the IC50 dose of each of the 3 drugs and performed gene expression profiling at each time point, comparing them to untreated cells.
We found that treatment with each of the 3 drugs resulted in 2-fold or higher down-regulation of the MYC-dependent proliferation pathway. The degree of down-regulation was progressively higher at each time point. Further, the degree of down-regulation was also associated with the selective inhibition of the PI3K pathway. The greatest inhibition of the pathway was observed in response to the selective PI3K pathway inhibitor, BKM120 (Figure 1A).
We evaluated the association of this pathway in 402 patients with DLBCL. The pathway was highly associated with survival (P<0.001, Figure 1B). These findings indicate that higher expression of the MYC-dependent proliferation pathway is a feature of tumors that have a poorer prognosis and down-regulation of that pathway could provide significant therapeutic benefit to those patients.
Through the testing of 3 separate drugs that target the PI3K pathway, we demonstrate that the approach is effective at physiologically achievable concentrations. Through a combination of gene expression profiling and examination of the downstream effects of the drug and expression profiles of patient tumors, our findings indicate that PI3K inhibitors inhibit lymphoma growth through the down-regulation of MYC-dependent proliferation. Our data provide the rationale for a clinical exploration of PI3K pathway inhibition as a therapeutic strategy in patients with lymphoma.
Rizzieri: Merck & Co., Inc.: Consultancy.
Walsh, KJ; Fan, S; Patel, A; Jacobs, CL; Smith, JL; Liu, Q; Rizzieri, DA; Dave, S
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