Dual ERK5 and AKT inhibition enhances the sensitivity of PTEN mutant triple negative breast cancer and glioblastoma cells to paclitaxel.
Session type: Poster / e-Poster / Silent Theatre session
New therapies for cancer are being developed that focus on specific mutations in a tumor rather than on the anatomic site of origin. The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) is important for the regulation of cell proliferation, growth, and survival. Loss of PTEN leads to activation AKT and subsequent ERK5 phosphorylation, which increases cell viability, proliferation, and chemoresistance. The mutation in PTEN is present in two very aggressive BT-549 triple negative breast cancer and U87MG glioblastoma cells.
To examine the crosstalk between the ERK5 and AKT signaling pathways, western blot analysis was performed to determine ERK5, AKT, cmyc, p21, and MEKK3 protein expression in U87 and BT-549 cells after treatment with ERK5 inhibitior XMD-8-92 and AKT inhibitor ipatasertib. MTT assay was used to determine the cell viability of U87 cells after treatment with ipatasertib, XMD-8-92, and paclitaxel for 72 hours. Synergy calculations were performed by Chou-Talalay method using Compusyn software. Ki67 and Hoechst immunofluorescence staining was performed in cells to determine cell proliferation.
1. Treatment with ipatasertib and XMD-8-92 decreased cell viability in PTEN mutant breast cancer and glioblastoma. Adding Ipatasertib and XMD-8-92 in a combination of 1:5 ratio significantly decreased cell viability compared to either inhibitor alone. 2. Significant decrease in the number of Ki67+/Hoechst+ cells were observed in BT-549 and U87 cells after treatment with ERK5 and AKT inhibitors. 3. Dual ERK5 and AKT inhibition enhanced the sensitivity of PTEN mutant cells to paclitaxel.
Dual ERK5 and AKT inhibition was synergistic in reducing cell viability and proliferation of PTEN mutant TNBC and GBM. Dual targeting of the AKT and ERK5 pathways enhanced the sensitivity of these cells to conventional chemotherapeutic agents. We conclude that new therapeutic interventions can be directed towards different cancers driven by the same mutation.