Inhibition of AKT By MK2206 but Not PI3-Kinase δ By Idelalisib Is Effective Against CLL Cells in an In Vitro Model of the Hypoxic Microenvironment

Treatment of chronic lymphocytic leukemia (CLL) relies on targeting the leukemic cells that populate the bone marrow and lymph nodes. Recent studies (Shachar, Cohen et al. 2012, Muz, de la Puente et al. 2014, Valsecchi, Coltella et al. 2016) suggest that the ability of CLL cells to adapt to low oxygen tensions, particularly within the bone marrow, may play an important role in their survival, proliferation and resistance to current therapies. Understanding the mechanisms underlying hypoxia-induced drug resistance may help to identify novel treatment strategies.

In this study, we compared the effects of the AKT inhibitor MK2206 and the PI3-kinase δ inhibitor idelalisib under in vitro conditions that mimic the hypoxic tumour microenvironment. MK2206 induced apoptosis of primary CLL cells in co-culture with stromal cells and caused a G0/G1 phase cell cycle arrest of OSU-CLL cells under both normoxic (21 % O₂) and hypoxic (1 % O₂) conditions. Consistent with other reports, no cytotoxic or cytostatic effects of idelalisib at clinically relevant doses were observed under these in vitro conditions. Treatment of both primary and OSU-CLL cells with MK2206 induced an accumulation of reactive oxygen species in the mitochondria and downregulated expression of P70-S6-kinase and Mcl-1, effects which were not observed following treatment with idelalisib.

Collectively these data suggest that the anti-apoptotic and cell cycle-regulatory roles of AKT in CLL cells may not be dependent on activity of the d-isoform of PI3-kinase within the hypoxic tumour microenvironment. The efficacy of MK2206 in vitro and the toxicities associated with idelalisib suggest further studies of MK2206 may be warranted, particularly for CLL patients with bulky disease.