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 Mills, Ana Maria Gonzalez-Angulo, Funda Meric-Bernstam

Research output: Contribution to journalArticle

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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
Externally publishedYes

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Biomarkers
Breast Neoplasms
Cell Line
Mutation
Paclitaxel
MK 2206
Small Interfering RNA
Neoplasms
Growth
Combination Drug Therapy
Heterografts
Transfection
Cell Cycle
Breast
Plasmids
Research Design
Phosphorylation
Cell Proliferation
Clinical Trials
Apoptosis

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Sangai, T., Akcakanat, A., Chen, H., Tarco, E., Wu, Y., Do, K. A., ... Meric-Bernstam, F. (2012). Biomarkers of rsponse to Akt inhibitor MK-2206 in breast cancer. Clinical Cancer Research, 18(20), 5816-5828. https://doi.org/10.1158/1078-0432.CCR-12-1141

Biomarkers of rsponse to Akt inhibitor MK-2206 in breast cancer. / Sangai, Takafumi; Akcakanat, Argun; Chen, Huiqin; Tarco, Emily; Wu, Yun; Do, Kim Anh; Miller, Todd W.; Arteaga, Carlos L.; Mills, Gordon; Gonzalez-Angulo, Ana Maria; Meric-Bernstam, Funda.

In: Clinical Cancer Research, Vol. 18, No. 20, 15.10.2012, p. 5816-5828.

Research output: Contribution to journalArticle

Sangai, T, Akcakanat, A, Chen, H, Tarco, E, Wu, Y, Do, KA, Miller, TW, Arteaga, CL, Mills, G, Gonzalez-Angulo, AM & Meric-Bernstam, F 2012, 'Biomarkers of rsponse to Akt inhibitor MK-2206 in breast cancer', Clinical Cancer Research, vol. 18, no. 20, pp. 5816-5828. https://doi.org/10.1158/1078-0432.CCR-12-1141
Sangai T, Akcakanat A, Chen H, Tarco E, Wu Y, Do KA et al. Biomarkers of rsponse to Akt inhibitor MK-2206 in breast cancer. Clinical Cancer Research. 2012 Oct 15;18(20):5816-5828. https://doi.org/10.1158/1078-0432.CCR-12-1141
Sangai, Takafumi ; Akcakanat, Argun ; Chen, Huiqin ; Tarco, Emily ; Wu, Yun ; Do, Kim Anh ; Miller, Todd W. ; Arteaga, Carlos L. ; Mills, Gordon ; Gonzalez-Angulo, Ana Maria ; Meric-Bernstam, Funda. / Biomarkers of rsponse to Akt inhibitor MK-2206 in breast cancer. In: Clinical Cancer Research. 2012 ; Vol. 18, No. 20. pp. 5816-5828.
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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.",
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AU - Wu, Yun

AU - Do, Kim Anh

AU - Miller, Todd W.

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N2 - 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.

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