Breast Tumor Cells with PI3K Mutation or HER2 Amplification Are Selectively Addicted to Akt Signaling

Abstract

BackgroundDysregulated PI3K/Akt signaling occurs commonly in breast cancers and is due to HER2 amplification, PI3K mutation or PTEN inactivation. The objective of this study was to determine the role of Akt activation in breast cancer as a function of mechanism of activation and whether inhibition of Akt signaling is a feasible approach to therapy.Methodology/Principal FindingsA selective allosteric inhibitor of Akt kinase was used to interrogate a panel of breast cancer cell lines characterized for genetic lesions that activate PI3K/Akt signaling: HER2 amplification or PI3K or PTEN mutations in order to determine the biochemical and biologic consequences of inhibition of this pathway. A variety of molecular techniques and tissue culture and in vivo xenograft models revealed that tumors with mutational activation of Akt signaling were selectively dependent on the pathway. In sensitive cells, pathway inhibition resulted in D-cyclin loss, G1 arrest and induction of apoptosis, whereas cells without pathway activation were unaffected. Most importantly, the drug effectively inhibited Akt kinase and its downstream effectors in vivo and caused complete suppression of the growth of breast cancer xenografts with PI3K mutation or HER2 amplification, including models of the latter selected for resistance to Herceptin. Furthermore, chronic administration of the drug was well-tolerated, causing only transient hyperglycemia without gross toxicity to the host despite the pleiotropic normal functions of Akt.Conclusions/SignificanceThese data demonstrate that breast cancers with PI3K mutation or HER2 amplification are selectively dependent on Akt signaling, and that effective inhibition of Akt in tumors is feasible and effective in vivo. These findings suggest that direct inhibition of Akt may represent a therapeutic strategy for breast and other cancers that are addicted to the pathway including tumors with resistant to Herceptin.

The transcriptional induction of PIK3CA in tumor cells is dependent on the oncoprotein Y-box binding protein-1

“…In accordance with our findings, She et al (2008) demonstrated that inhibition of AKT1/2 in HCC1806, a triple-negative cell line with wild-type PIK3CA, did not reduce P-S6RP (S235/236) despite the fact that P-AKT (S473) and p70S6K (T389) levels The YB-1/PIK3CA/uPA network promotes invasion A Astanehe et al were decreased. We suspect this is because RSK remains activated.…”

“…Interestingly, She et al (2008) used a potent inhibitor of AKT1 and AKT2 (AKTi-1/2) on various breast cancer cell lines and demonstrated that those with wild-type PIK3CA, including MDA-MB-231 that were used in our studies, were resistant to the effect of AKTi-1/2 even at concentrations leading to complete loss of P-AKT, whereas cells with PIK3CA mutations or HER2 amplifications were uniformly sensitive. They concluded that cells with PIK3CA mutations are dependent on AKT signaling whereas those with wild-type PIK3CA are not.…”

MK-2206, an Akt inhibitor, enhances carboplatinum/paclitaxel efficacy in gastric cancer cell lines

“…Treatment with MK-2206 first might lead to the accumulation of G 1 -phase cells limiting the activity of Mphase-specific chemotherapy. 14 Gastric cancer, similar to other malignancies, is a genetically heterogeneous disease: Inhibition of one pathway is never sufficient as other pathways often compensate. Our results show that common molecular findings in human malignancies.…”

Association of FABP5 Expression With Poor Survival in Triple-Negative Breast Cancer

“…Of these seven cell lines, the three with the highest levels of FABP5 mRNA (Hs578T, HTB-129, and MDA-MB231) have been reported to be negative for ER and PR. 26,27 MDA-MB231 is also negative for HER2, 27 but the HER2 status of HTB-129 and Hs578T is not known.…”