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

SummaryBreast 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 inPIK3CA (PI3K catalytic subunit alpha) mutated (E545K) cells (MCF-7 and MDA-MB-361) than inPIK3CA wild-type cells (HCC38), which implied there is a relationship betweenPI3K genetic status and the efficacy of combination therapy. By usingPIK3CA 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 ofPIK3CA E545K alleles to wild-type sequence in MCF-7 cells dramatically impaired the synergy of PI3Ki&AMPKa (combinatorial PI3K inhibition and AMPK ac...
Source: Investigational New Drugs - Category: Drugs & Pharmacology Source Type: research