PI3Kalpha的药理学激活在代谢应激下触发癌细胞死亡

Cancer cells maintain oncogenic signalling within a survival “fitness zone”. While conventional targetalphaed therapies suppress this signalling below a critical threshold, excessive activation of the same pathways can also be lethal to cell, an observation currently being explored as a novel therapeutic approach in cancer. In this study, we report that hyperactivation of PI3Kalpha, one of the most frequently oncogenically activated PI3K isoforms, using the small-molecule PI3Kalpha activator UCL-TRO-1938 (further referred to as 1938) induces cytotoxicity in cancer cell lines while sparing non-transformed cells. This PI3K activation-induced cell death (PI3K-AICD) depends on AKT/mTORC1 activity, only occurs under serum starvation and is enhanced by low O 2 levels. This hyperactivation lethality is mechanistically linked to an irreconcilable metabolic conflict by simultaneously activating anabolic PI3K/mTORC1 signalling in a catabolic (hypoxic) state, resulting in an unresolvable energy crisis and ultimately cell death. In serum-deprived lung cancer cell lines, 1938 induces a magnified endoplasmic reticulum stress response which, along with PI3K-AICD, can be mitigated by supplementation with unsaturated fatty acids, suggesting a critical metabolic dependency on lipid metabolism for driving this cell death response. Consequently, co-treatment with 1938 and inhibitors of stearoyl-CoA desaturase-1 (SCD1), an O 2 -dependent enzyme essential for fatty acid desaturation, amplifies the PI3K-AICD response. In summary, these findings demonstrate that enhancing an oncogenic pathway central to metabolic control can selectively kill cancer cells.