Abstract 3494: Combining ATRA and GSK3 inhibition in AML

Abstract

Abstract Acute Myeloid Leukemia (AML) is the most common form of leukemia in adults. Unfortunately, the standard therapeutic agents used for this disease have high toxicities and poor efficacy. The one exception to these poor outcomes is the use of all-trans retinoic acid (ATRA) for a rare subtype of AML (APL, 5-10% of AML). The use of the differentiation agent, ATRA, in combination with low dose chemotherapy leads to the long term survival and presumed cure of 75-85% of patients. Unfortunately ATRA is not clinically useful for other subtypes of AML. Though the non-APL leukemic cells also express retinoic acid receptors (RAR), they require significantly higher concentrations of ATRA for effective differentiation. The requirement for high doses of ATRA for differentiation is at least partially due to the fact that ATRA initiates a negative feedback loop resulting in the degradation of RAR. This feedback loop limits the magnitude and duration of its effects. Despite the high clinical significance of inhibiting the degradation of RAR to enhance the efficacy of ATRA, little is known about the pathways leading to RAR degradation. Our data suggests that the kinase, GSK3, plays a role in RAR degradation. Utilizing genetic and biochemical approaches with AML cell lines and mouse xenograft studies, we have identified that inhibition of GSK3 in combination with ATRA is a promising strategy to induce AML differentiation and growth inhibition. For example, the combination of ATRA and GSK3 inhibitors including Lithium and SB415286 leads to a significant enhancement in anti-tumor activity in a mouse AML xenograft model system. Mechanistically, our data suggests that GSK3 enhances ATRA activity through modulating the expression of RAR. Utilizing HL-60 cells, we have found that not only can endogenous GSK3 and RAR physically interact, but GSK3 can directly phosphorylate RAR and modulate its stability. After the addition of GSK3 inhibitors, the interaction with RAR is disrupted and the GSK3-mediated phosphorylation of RAR is blocked. Overall, our studies suggest the clinical potential of ATRA and GSK3 inhibition for AML and provide a mechanistic framework to explain the promising activity of this combination regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3494. doi:10.1158/1538-7445.AM2011-3494