The Novel Phospholipid Mimetic KPC34 Is Highly Active Against Acute Myeloid Leukemia with Activated Protein Kinase C

Abstract

Acute myeloid leukemia (AML) is an aggressive malignancy with poor outcomes. Nucleoside analogs are subject to resistance mechanisms including downregulation of equilibrative nucleoside transporter (ENT1) and deoxycytidine kinase (dCK). KPC34 is a novel phospholipid mimetic that when cleaved by phospholipase C (PLC) liberates gemcitabine monophosphate and a diacylglycerol mimetic that inhibits the classical isoforms of protein kinase C (PKC). KPC34 acts independently of ENT1 and dCK. KPC34 was active against all AML cell lines tested with IC50s in the nanomolar range. Enforced expression of PLC increased response to KPC34 in vivo. In an orthotopic, xenograft model, KPC34 treatment resulted in a significant increase in survival compared to control animals and those treated with high-dose cytarabine. In a PDX model with activated PKC, there was a significant survival benefit with KPC34, and at progression, there was attenuation of PKC activation in the resistant cells. In contrast, KPC34 was ineffective against a syngeneic, orthotopic AML model without activated PKC. However, when cells from that model were forced to express PKC, there were significantly increased sensitivity in vitro and survival benefit in vivo. These data suggest that KPC34 is active against AML and that the presence of activated PKC can be a predictive biomarker.