Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.

Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA, Miller TW, Arteaga CL, Mills GB, Gonzalez-Angulo AM, Meric-Bernstam F
Clin Cancer Res. 2012 18 (20): 5816-28

PMID: 22932669 · PMCID: PMC3772348 · DOI:10.1158/1078-0432.CCR-12-1141

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.

©2012 AACR

MeSH Terms (18)

Animals Apoptosis Biomarkers, Pharmacological Breast Neoplasms Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases Drug Synergism Female Heterocyclic Compounds, 3-Ring Humans In Vitro Techniques Mice Oncogene Protein v-akt Paclitaxel Phosphatidylinositol 3-Kinases Protein Kinase Inhibitors PTEN Phosphohydrolase Transplantation, Heterologous

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