Biomarkers of rsponse to Akt inhibitor MK-2206 in breast cancer

Takafumi Sangai, Argun Akcakanat, Huiqin Chen, Emily Tarco, Yun Wu, Kim Anh Do, Todd W. Miller, Carlos L. Arteaga, Gordon B. Mills, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam

    Research output: Contribution to journalArticle

    93 Scopus citations

    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.

    Original languageEnglish (US)
    Pages (from-to)5816-5828
    Number of pages13
    JournalClinical Cancer Research
    Volume18
    Issue number20
    DOIs
    StatePublished - Oct 15 2012

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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