Abstract P4-08-21: Development of novel inhibitors of the serum/glucocorticoid induced kinase (SGK) family to address limitations of AKT/PI3K/mTOR inhibitors in breast cancer

Abstract

Abstract Activation of the AKT/PI3K/mTOR signaling through genetic and epigenetic mechanisms is a frequent event in all subtypes of breast cancer, and it is associated with resistance to various therapies. Development of inhibitors targeting this pathway has been met with limited success so far, mainly due to various feedback and crosstalk mechanisms amongst different members of the pathway. Several therapies that target the PI3K pathway have also been associated with dose limiting toxicities such as hyperglycemia, hyperinsulinemia, skin rashes and infections, limiting their use. The SGK family of kinases has recently been implicated in the resistance to AKT and PI3K inhibitors by promoting AKT-independent signaling to maintain the activation of the AKT/PI3K/mTOR pathway. The SGK and AKT families share similar domain structures as well as upstream activators such as PDK1 and mTORC2, and downstream effectors such as TSC2, FOXO3, and GSK3B, providing a strong rationale for the development of inhibitors targeting the SGK family. Here we present the development of novel small molecule ATP-competitive inhibitors of the SGK family. Several compounds displayed low nanomolar affinity towards SGK1 in whole cell assays, with IC50s ranging between 10-100 nM, which is 30-300 folds and 80-1000 folds higher than the previously characterized SGK1 inhibitors GSK650394 and EMD638683, respectively, as well as good selectivity against related AGC family kinases. Experiments in cells have shown a strong dose-dependent decrease in the phosphorylation of its downstream target NDRG1 at sub-micromolar concentrations, confirming selective targeting of SGK1 in whole cells. Single agent activity of SGK1 inhibition was modest in different cancer cell lines, with IC50 values for inhibition of their proliferation ranging from 1-10 uM, in agreement with the role of the SGK family in regulation of stress-induced signaling and not normal cell proliferation. However, combinations of SGK with AKT inhibitors displayed strong synergies in different breast cancer cell lines, especially in cells with resistance to AKT/PI3K inhibitors. For example, strong Bliss synergy index scores > 18 were obtained with different SGK1 inhibitors when combined with either AKT inhibitors MK-2206, ipatasertib, or capivasertib, in the JIMT-1 breast cancer cell line, which is a model of resistance to AKT, PI3K, and HER2-directed therapies. These results suggest that the combination of SGK with AKT inhibitors could be an effective therapeutic strategy to alleviate toxicities associated with AKT/PI3K/mTOR inhibitors by lowering their required dose, while maintaining anti-tumor activity and delaying the development of resistance. Citation Format: Delphine Labit, Sabindra Pradhananga, Maroua Khalifa, Emma Blackburn, Naheed Sajid, Marc Vidal, Debra Odink, Eric Campeau. Development of novel inhibitors of the serum/glucocorticoid induced kinase (SGK) family to address limitations of AKT/PI3K/mTOR inhibitors in breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-08-21.