Abstract LB-115: Mechanisms of acquired resistance to allosteric versus ATP-competitive AKT inhibition

Abstract

Abstract The PI3K/AKT signaling pathway mediates a variety of cellular processes including metabolism, glucose uptake, angiogenesis, growth, survival and proliferation. Increased activity of this pathway is observed in many cancer types and is associated with tumor invasiveness, survival, and proliferation. Various regulators of this pathway are being investigated as therapeutic targets in oncology, including the AKT kinases. Two distinct classes of AKT inhibitors (AKTi) are being evaluated as therapeutic agents in the clinic: allosteric inhibitors (e.g. MK-2206) and ATP-competitive inhibitors (e.g. Ipatasertib/GDC-0068). In an effort to elucidate pathway alterations in response to these inhibitors and, ultimately, to improve therapeutic outcome, we are currently evaluating mechanisms of acquired resistance to both AKT inhibitor classes. The establishment of clonal cell populations resistant to either MK-2206 or GDC-0068 and subsequent characterization of alterations in these lines revealed various genetic and non-genetic variations associated with AKTi resistance. Here, we will present findings on biological mechanisms that contribute to acquired AKTi resistance in prostate and ovarian cancer cell line models. Citation Format: Kristin M. Zimmerman, Brian Lee, Wei-Jen Chung, Florian Gnad, Eva Lin, Scott Martin, Kui Lin. Mechanisms of acquired resistance to allosteric versus ATP-competitive AKT inhibition. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-115.