Abstract 669: Combined inhibition of AKT & TBK1 for the treatment of breast cancer

Abstract

Abstract Breast cancer (BC) is the most frequently diagnosed malignancy and the second leading cause of cancer mortality in Western women. 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. This pathway regulates multiple cellular processes to promote BC development, growth, metastasis, and drug resistance. Consequently, over 100 clinical trials are currently underway worldwide to evaluate the therapeutic efficacy of PI3K and AKT inhibitors in BC; however, initial data reported so far 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 mapped TRAF2 phosphorylation sites (Ser-11 and Ser-55), identified PKC and TBK1 are the relevant kinases, and reported that TRAF2 phosphorylation enhances NF-κB activation to promote cancer cell survival under conditions of cellular stresses. Recently, we discovered that inhibition of AKT leads to increased phosphorylation of TRAF2 at Ser-11 by TBK1 in 4 out of 6 commonly used BC cell lines. TBK1 (aka T2K for TRAF2-associated kinase) and its close homologue IKKϵ are serine/threonine kinases overexpressed in ~70% of BC and play critical roles in BC cell survival. Interestingly, all 4 BC cell lines that exhibited enhanced TRAF2 phosphorylation were completely resistant to AKT inhibition-induced apoptosis in vitro, and combined inhibition of both AKT and TBK1/IKKϵ synergistically induced apoptosis in these BC lines. Importantly, combined inhibition of AKT and TBK1/IKKϵ also significantly suppresses xenograft BC tumor growth in vivo. Mechanistically, AKT did not directly inhibit TBK1, IKKϵ or TRAF2; it seems that an unknown kinase suppressed by AKT in cancer cells in normal culture conditions enhances TBK1-mediated TRAF2 Ser-11 phosphorylation in BC cells upon AKT inhibition. Nevertheless, our data suggest that inhibition of the PI3K-AKT pathway derepresses the pro-survival TBK1-TRAF2 pathway, which in turn confers resistance to PI3K-AKT inhibition in BC, and that combined inhibition of AKT and TBK1 effectively suppresses BC tumor growth. These findings also provide strong rationales for PDX and clinical investigation of combined AKT and TBK1 inhibition for the treatment of human BCs. Citation Format: Hasem Habelhah, Laiqun Zhnag. Combined inhibition of AKT & TBK1 for the treatment of breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 669.