Synergistic Effects of PI3K and c-Myc Co-targeting in Acute Leukemia: Shedding New Light on Resistance to Selective PI3K-δ Inhibitor CAL-101.

Enthusiasms into the application of PI3K-δ inhibitor CAL-101 has been muted due to the over-activation of compensatory molecules. Our results delineated that c-Myc suppression using 10058-F4 enhanced CAL-101 cytotoxicity in less sensitive cells through different mechanisms based on p53 status; while CAL-101-plus-10058-F4 induced G1 arrest in wild-type p53-expressing leukemic cells, no conspicuous increase in G1 was noted in U937 cells harboring mutant p53. Conclusively, this study shed lights on the role of c-Myc oncoprotein in acute leukemia cells sensitivity to PI3K inhibitor and outlined that the combination of c-Myc inhibitor and CAL-101 may be a promising therapeutic approach in leukemia.

Small molecule inhibitor of c-Myc 10058-F4 inhibits proliferation and induces apoptosis in acute leukemia cells, irrespective of PTEN status.

Based on the frequent over-expression of c-Myc in hematologic malignancies and its crucial role in the regulation of diverse oncogenic pathways involved in leukomogenesis, intense interest has recently focused on this factor as an appealing therapeutically target in leukemia. In the present study, we aimed to investigate the anti-leukemic property of small molecule inhibitor of c-Myc 10058-F4 in two distinct acute leukemia cell lines consist of acute promyelocytic leukemia (APL)-derived NB4 cells (with wild-type PTEN) and acute lymphoblastic leukemia (ALL)-derived Nalm-6 cells (with down-regulated PTEN). 10058-F4 effectively reduced survival of leukemic cells; however, we found a different cell sensitivity pattern in the tested cell lines. To the best of our knowledge, no study has addressed the underlying mechanisms responsible for leukemic cell resistance to 10058-F4, and we propose for the first time that the effectiveness of c-Myc inhibition might be attenuated through over-activated phosphoinositide 3-kinase (PI3K) in less sensitive Nalm-6 cells. Notably, we failed to find an obvious correlation between PTEN status and cell sensitivity to the inhibitor in a panel of hematologic malignant cells. Beyond 10058-F4 cytotoxicity as a single agent, synergistic experiments also delineated that pharmaceutical targeting of c-Myc could potentiate the anti-cancer effect of both vincristine and Arsenic trioxide in ALL and APL cells, respectively. In conclusion, this study sheds light on the potent anti-leukemic characteristics of 10058-F4 and provide an interesting evidence to the application of this agent in combination with PI3K inhibitors especially in acute leukemia with over-activated PI3K, irrespective of PTEN status.