期刊
CLINICAL CANCER RESEARCH
卷 18, 期 20, 页码 5816-5828出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-12-1141
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资金
- Susan G. Komen Foundation [SAC10006]
- Stand Up To Cancer Dream Team Translational Cancer Research Grant, a Program of the Entertainment Industry Foundation [SU2C-AACR-DT0209 01]
- Society of Surgical Oncology Clinical Investigator Award in Breast Cancer Research
- NIH [R21 CA159270-01, F32CA121900, K99CA142899]
- National Center for Research Resources [3UL1RR024148, UL1TR000371]
- The University of Texas MD Anderson Cancer Center [P30 CA016672]
- Breast Cancer Specialized Program of Research Excellence (SPORE) [P50CA98131]
- Vanderbilt-Ingram Cancer Center [P30CA68485]
- Breast Cancer Research Foundation
- ACS [CRP-07-234]
- Lee Jeans Translational Breast Cancer Research Program
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. Clin Cancer Res; 18(20); 5816-28. (C) 2012 AACR.
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