Abstract 4616: TBK1 and GSK3 mediated TRAF2 phosphorylation confers resistance to PI3K-AKT inhibition in breast cancer cells

Abstract

Abstract Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in Western women. As is the case for most other solid tumors, metastasis and drug resistance are the main causes of death. In ~80% of BC cases, the PI3K-AKT pathway is aberrantly activated, due to the alterations in genes encoding the pathway components, such as Ras, Her2, PTEN, PIK3C and AKT. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic efficacy of PI3K and AKT inhibitors in BC; however, initial data revealed that inhibition of this pathway is either not effective or often results in development of resistance and relapse of the disease. Thus, identification of additional targets and therapeutic combinations are urgently needed. We previously reported that TBK1-mediated TRAF2 Ser-11 phosphorylation enhances NF-κB activation to promote cancer cell survival under conditions of cellular stresses. Recently, we discovered that GSK3β directly phosphorylates TRAF2 at Thr-7 upon Ser-11 phosphorylation by TBK1, and that phosphorylation of both Thr-7 and Ser-11 is essential for sustained NF-κB activation and BC cell resistance to PI3K-AKT inhibition. TBK1 and its close homologue IKKε are overexpressed in ~70% of BC and play critical roles in BC cell survival. GSK3β is a constitutively active kinase activity in unstimulated normal cells, but its activity is suppressed in most cancer cell types by AKT-mediated phosphorylation. These published reports and our new findings suggest that inhibition of AKT in BC cells leads to increased phosphorylation of TRAF2 by TBK1 and GSK3β, which confers resistance to PI3K-ATK inhibition. Bioinformatic analyses revealed that TRAF2 and GSK3β are also overexpressed in invasive BC, and significantly correlate with poor prognosis. As expected, inhibition of both AKT and TBK1 or GSK3b synergistically induced apoptosis in BC cell lines in vitro and significantly suppressed xenograft BC tumor growth in vivo. Thus, our data suggest that further investigation of the efficacies of combined PI3K/AKT and TBK1/GSK3β inhibition in PDX models of BC has the potential to develop new strategies for BC treatment. Citation Format: Hasem Habelhah, Laiqun Zhang. TBK1 and GSK3 mediated TRAF2 phosphorylation confers resistance to PI3K-AKT inhibition in breast cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4616.