Targeting the PI3K/AKT pathway in cancer using a pan-AKT degrader

点击翻译按钮获取中文摘要

Abstract The serine/threonine kinase AKT is a central component of the phosphoinositide 3-kinase (PI3K) signaling pathway and a key regulator of many cellular processes including cell growth, proliferation, and metabolism. Aberrant activation of the PI3K/AKT pathway disrupts normal regulation of proliferation and survival, resulting in tumorigenesis. AKT is hyperactivated in over 50% of human tumors, making it one of the most frequent molecular perturbations in cancer. Several ATP-competitive, allosteric, and covalent pan-AKT inhibitors have been developed and are currently under clinical investigation. However, robust therapeutic responses to AKT inhibition have not been observed. We hypothesized that reducing cellular AKT protein levels via targeted protein degradation could enhance the ability to kill cells dependent on AKT signaling. Heterobifunctional degrader molecules, also known as a PROTACs (proteolysis targeting chimeras), recruit an E3 ubiquitin ligase into close proximity with the target protein to induce its ubiquitination and subsequent proteasomal degradation. We developed INY-03-041, a pan-AKT degrader consisting of the AKT inhibitor, GDC-0068, chemically conjugated to lenalidomide, a recruiter of the E3 ubiquitin ligase Cereblon. Protein degraders display several advantages over inhibitors, including enhancing selectivity of multi-targeted inhibitors, abrogating kinase-independent functions, and overcoming resistance mutations. INY-03-041 induces potent and selective degradation of all three AKT isoforms, and exhibits enhanced anti-proliferative effects compared to GDC-0068 in breast cancer cells. The hypothesis driving this application is that targeted AKT degradation will inhibit cancer cell growth more robustly than AKT inhibition, leading to durable responses in vivo, and will be a valuable tool to identify novel biological functions of AKT. In Aim 1 I will evaluate the consequences of INY-03-041-mediated AKT degradation on cell signaling, proliferation, and survival. The goal of this aim is to uncover novel functions of AKT after acute protein depletion, and to identify genetic or epigenetic biomarkers for sensitivity to AKT degradation, which may inform therapeutic indications for AKT degradation. In Aim 2 I will investigate INY-03-041-induced AKT degradation in vivo to determine if AKT depletion may be a viable therapeutic modality. In summary, this proposal aims to investigate the functional consequences of AKT degradation, and to use INY-03-041 as a chemical probe to study the effects of acute AKT depletion. The proposed studies are not only discovery-based, but highlight a novel method to decode the pleiotropic mechanisms that govern AKT signaling in human cancer.