Biomarkers of Response to Akt Inhibitor MK-2206 in Breast Cancer

Abstract

Purpose We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity. Experimental Design MK-2206 effects on cell signaling were assessed in vitro and in vivo. Its antitumor efficacy was assessed in vitro in a panel of cancer cell lines with differing PIK3CA and PTEN status. Its in vivo efficacy was tested as a single agent and in combination with paclitaxel. Results MK-2206 inhibited Akt signaling and cell-cycle progression, and increased apoptosis in a dose-dependent manner in breast cancer cell lines. Cell lines with PTEN or PIK3CA mutations were significantly more sensitive to MK-2206; however, several lines with PTEN/PIK3CA mutations were MK-2206 resistant. siRNA knockdown of PTEN in breast cancer cells increased Akt phosphorylation concordant with increased MK-2206 sensitivity. Stable transfection of PIK3CA E545K or H1047R mutant plasmids into normal-like MCF10A breast cells enhanced MK-2206 sensitivity. Cell lines that were less sensitive to MK-2206 had lower ratios of Akt1/Akt2 and had less growth inhibition with Akt siRNA knockdown. In PTEN-mutant ZR75-1 breast cancer xenografts, MK-2206 treatment inhibited Akt signaling, cell proliferation, and tumor growth. In vitro, MK-2206 showed a synergistic interaction with paclitaxel in MK-2206–sensitive cell lines, and this combination had significantly greater antitumor efficacy than either agent alone in vivo. Conclusions MK-2206 has antitumor activity alone and in combination with chemotherapy. This activity may be greater in tumors with PTEN loss or PIK3CA mutation, providing a strategy for patient enrichment in clinical trials.

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…Interestingly, catalytic AKT inhibitors (e.g., GDC-0068 and AZD5363) have inhibitory effects in cell lines with AKT1 mutations (E17K) and AKT3 fusions, whereas allosteric inhibitors (e.g., MK-2206) do not (58,59). MK-2206, AZD5363, and GDC-0068 have all demonstrated increased activity in cell lines with PIK3CA or PTEN alterations (60)(61)(62). This may imply that there is a stronger rationale for AKT inhibitors in tumors with PTEN alterations than pan-PI3K inhibitors.…”

Molecularly targeting the PI3K-Akt-mTOR pathway can sensitize cancer cells to radiotherapy and chemotherapy

“…Recently, many small molecular inhibitors targeting intracellular kinases of the PI3K-Akt-mTOR pathway, such as MK2206 for Akt, and AZD8055 for mTOR, were developed ( Fig. 1) [52,53]. However, both preclinical and clinical trials clearly demonstrated the resistance of cancer patients to these molecularly targeted therapies, raising new challenges for eradicating human cancers [10,11].…”

The regulatory roles of phosphatases in cancer

“…Screening for PTEN mutations may identify BC patients who may benefit from treatment with AKT inhibitors. In this regard, BC cell lines with PTEN mutations were recently described to have increased sensitivity to the novel AKT inhibitor MK-2206 (235).…”