Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.
Biomarkers of response to Akt inhibitor MK-2206 in breast cancer.
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DOI：
10.1158/1078-0432.ccr-12-1141
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发表时间：
2012-10-15
期刊：
影响因子：
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通讯作者：
Meric-Bernstam F
中科院分区：
文献类型：
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作者：
Sangai T;Akcakanat A;Chen H;Tarco E;Wu Y;Do KA;Miller TW;Arteaga CL;Mills GB;Gonzalez-Angulo AM;Meric-Bernstam F
我们验证了变构Akt抑制剂MK-2206抑制肿瘤生长的假设，以及PTEN/PIK3CA突变赋予MK-2206敏感性。在体外和体内评估MK-2206对细胞信号传导的影响。在具有不同PIK3CA和PTEN状态的一组癌细胞中，体外评估了其抗肿瘤功效。分别进行了单用和与紫杉醇合用的体内药效试验。MK-2206抑制Akt信号通路和细胞周期进程，并以剂量依赖性方式增加乳腺癌细胞系的凋亡。PTEN或PIK3CA突变的细胞系对MK-2206的敏感性显著提高；然而，一些PTEN/PIK3CA突变的品系对MK-2206具有抗性。乳腺癌细胞中siRNA敲低PTEN会增加Akt磷酸化，这与MK-2206敏感性增加一致。将PIK3CA E545K或H1047R突变质粒稳定转染到正常样MCF10A乳腺细胞中可增强MK-2206的敏感性。对MK-2206不敏感的细胞系具有较低的Akt1/Akt2比例，并且Akt siRNA敲低对生长的抑制作用较小。在pten突变的ZR75-1乳腺癌异种移植物中，MK-2206治疗抑制Akt信号传导、细胞增殖和肿瘤生长。在体外实验中，MK-2206与紫杉醇在MK-2206敏感细胞系中表现出协同作用，且在体内联合使用的抗肿瘤效果明显高于单独使用。MK-2206单独或联合化疗均具有抗肿瘤活性。在PTEN缺失或PIK3CA突变的肿瘤中，这种活性可能更大，这为临床试验中的患者富集提供了一种策略。
We tested the hypothesis that allosteric Akt inhibitor MK-2206 inhibits tumor growth, and that PTEN/PIK3CA mutations confer MK-2206 sensitivity. 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. 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. 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.