PIK3CA mutation sensitizes breast cancer cells to synergistic therapy of PI3K inhibition and AMPK activation

被引:12
作者
Liu, Songlin [1 ]
Tang, Yunhong [1 ]
Yan, Maomao [2 ]
Jiang, Weixi [1 ]
机构
[1] Cent South Univ, Xiangya Hosp, Dept Neurosurg, 87 Xiangya Rd, Changsha 410008, Hunan, Peoples R China
[2] Emory Univ, Dept Pharmacol, 1510 Clifton Rd, Atlanta, GA 30322 USA
关键词
PIK3CA mutation; AMPK; AICAR; PI3K; Precision therapy; Combination therapy; PATHWAY INHIBITORS; RESISTANCE; APOPTOSIS; GDC-0941; PROLIFERATION; KINASE; GROWTH; GENES; CYCLE;
D O I
10.1007/s10637-018-0563-3
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Breast cancer has been emerging as a most common threat among women, thus many efforts were made to find drugs for fighting breast cancer. So far, PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) inhibitors have been believed to be effective drugs until frequent resistance emerged. Recently, PI3K H1047R mutation has been reported to sensitize breast cancer cells to PI3K inhibition by aspirin. Considering aspirin activates AMPK (AMP-activated protein kinase) simultaneously, it is possible that AMPK activators and PI3K inhibitors can synergistically inhibit breast cancers. Here we clearly observed synergistic suppression of cell growth in all three breast cancer cell lines (MCF-7, MDA-MB-361 and HCC38) when co-treating cells with PI3K inhibitor GDC-0941 and AMPK activator AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide). What is more, it is rather remarkable that the synergistic effect was much more dramatic in PIK3CA (PI3K catalytic subunit alpha) mutated (E545K) cells (MCF-7 and MDA-MB-361) than in PIK3CA wild-type cells (HCC38), which implied there is a relationship between PI3K genetic status and the efficacy of combination therapy. By using PIK3CA wild-type isogenic MCF-7 cell line, which exhibited attenuated cell proliferation compared with the parental MCF-7 cell line, we found endogenous reverse mutation of PIK3CA E545K alleles to wild-type sequence in MCF-7 cells dramatically impaired the synergy of PI3Ki&AMPKa (combinatorial PI3K inhibition and AMPK activation). Furthermore, PI3Ki&AMPKa significantly attenuated tumorigenesis of parental MCF-7 cells but not PIK3CA wild-type isogenic MCF-7 cells in tumor xenograft models. Taken together, our results suggest a promising precision therapy of PI3Ki&AMPKa in PIK3CA mutant breast cancers.
引用
收藏
页码:763 / 772
页数:10
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