The phosphatidylinositol‐3 kinase I inhibitor BKM120 induces cell death in B‐chronic lymphocytic leukemia cells in vitro

BKM120, a pan class I PI3K inhibitor, was cytotoxic in the majority of primary B‐chronic lymphocytic leukemia (CLL) lymphocytes, including samples from patients who have a high‐risk for poor response to treatment (patient with del11 and del17) at clinically obtainable concentrations. The PI3Kδ inhibitor Cal‐101 is cytotoxic in B‐CLL lymphocytes in vitro and is active in the treatment of CLL in vivo. Interestingly, we demonstrated that BKM120 is 3.6 fold more toxic than Cal‐101 in malignant B‐CLL lymphocytes in vitro. BKM120 cytotoxicity correlated with the basal expression of proteins involved in the PI3K/Akt pathway. A protein signature of PI3K pathway proteins predicts the response to BKM120 treatment. In the primary B‐CLL lymphocytes tested in vitro, BKM120 decreased the phosphorylation status of molecular biomarkers used as indicators of PI3K pathway inhibition in vivo. Also, BKM120 induced apoptosis in primary B‐CLL cells culture in the presence and absence of stromal cell support. Our findings suggest that BKM120 should be tested clinically in CLL. What's new? None of the standard treatments for chronic lymphocytic leukemia (CLL) result in curative therapy. In view of the critical role of PI3K in CLL homeostasis, here the authors examine the activity of the pan class I PI3K inhibitor BKM120. They find that clinically achievable concentrations of BKM120 have antitumor activity in CLL lymphocytes associated with down‐regulation of the PI3K pathway in vitro. They identify a protein signature predicting BKM120 sensitivity in CLL lymphocytes. Moreover, BKM120 presents significantly greater cytotoxicity than the PI3Kδ inhibitor Cal‐101, which is especially relevant since Cal‐101 has known antitumor activity in relapsed CLL patients.