Vertical inhibition of the PI3K/Akt/mTOR pathway is synergistic in breast cancer

Abstract

Deregulation and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian (or mechanistic) target of rapamycin (mTOR) pathway have a major role in proliferation and cell survival in breast cancer. However, as single agents, mTOR inhibitors have had modest antitumor efficacy. In this study, we evaluated the effects of vertical inhibition of mTOR and Akt in breast cancer cell lines and xenografts. We assessed the effects of mTOR inhibitor rapamycin and Akt inhibitor MK-2206, given as single drugs or in combination, on cell signaling, cell proliferation and apoptosis in a panel of cancer cell lines in vitro. The antitumor efficacy was tested in vivo. We demonstrated that MK-2206 inhibited Akt phosphorylation, cell proliferation and apoptosis in a dose-dependent manner in breast cancer cell lines. Rapamycin inhibited S6 phosphorylation and cell proliferation, and resulted in lower levels of apoptosis induction. Furthermore, the combination treatment inhibited phosphorylation of Akt and S6, synergistically inhibited proliferation and induced apoptosis with a higher efficacy. In vivo combination inhibited tumor growth more than either agent alone. Our data suggest that a combination of Akt and mTOR inhibitors have greater antitumor activity in breast cancer cells, which may be a viable approach to treat patients.

Human Pancreatic Cancer Cells Undergo Profound Metabolic Reprogramming Towards Cellular Stemness as Adaptation to Inhibition of the Akt Pathway

“…Samples were loaded in protein gels based on total protein content followed by Ponceau S staining, as standard housekeeping proteins frequently used as loading controls were also differentially regulated in our proteomic data. We confirmed by western blot that mTOR expression was increased in all adapted cells ( Figure 2F), as mTOR activation is a known escape mechanism from AKT inhibition (Woo et al, 2017), and a major coordinator of mitochondrial activities, protein synthesis and proliferation (Morita et al, 2015). Overall, differential expression of the mitochondrial proteins TFB2M, SSBP1 HADHA and VDAC1 was generally confirmed ( Figure 2F).…”

Blocking PI3K/AKT signaling inhibits bone sclerosis in subchondral bone and attenuates post‐traumatic osteoarthritis

“…Although the subchondral bone-cartilage interplay is believed to contribute strongly to OA progression (Chen et al, 2017;Hayami et al, 2004;Zhen et al, 2013), the potential molecular signaling for the subchondral bone-cartilage interaction has been rarely investigated.…”

“…Various signaling pathways have been found involved in the OA progression, and the modulatory role of the phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB), or AKT signaling in the pathogenesis process of OA has received substantial attentions (Chen, Wu, Sun, Dong, & Zhao, 2016;Chen et al, 2017;Dong et al, 2016). An upregulation of PI3K/AKT signaling in synovial fibroblasts of OA patients was recently reported (Chen, Hou, Hou, & Liu, 2014).…”

PLCA8 suppresses breast cancer apoptosis by activating the PI3k/AKT/NF‐κB pathway

“…Thus, PI3K/Akt pathway‐related transduction, including its mechanisms of activation, signal‐transducing molecules and effects on gene expression, contributes to tumorigenesis. Abnormal activation of the PI3k/AKT pathway is observed in numerous solid tumours, including BC, and this pathway controls a series of cellular processes, including cell proliferation, cell cycle, apoptosis, autophagy and cell migration. For example, miR‐613 acts as an upstream regulator that disturbs the interaction between YAP and WBP2, influencing the activity of the EGFR/PI3K pathway in triple‐negative BC cells .…”