Inavolisib在子宫内膜样子宫内膜癌临床前模型中显示抗增殖作用

Objectives: Phosphoinositide 3-kinase (PI3K) is a key intracellular signaling enzyme that regulates cell growth, survival, and metabolism. Genetic alterations in the PIK3CA pathway are among the most common molecular events in endometrial cancer (EC), occurring in up to 80% of cases. Inavolisib is a highly selective PI3K-alpha inhibitor, and promotes the degradation of mutated p110alpha, the catalytic subunit encoded by PIK3CA. It has shown promising antitumorigenic activity in preclinical and clinical models of multiple solid tumors including endocrine resistant breast cancer. Endometrioid EC is the most common subtype of EC, one of the only cancers for which both incidence and mortality continue to rise. The backbone of its adjuvant treatment consists of a platinum-doublet, but new therapies are urgently needed. We aimed to investigate the effects of inavolisib on cell proliferation, cellular stress, apoptosis, cellular adhesion and migration in endometrioid EC cell lines. Methods: The human endometrioid EC cell lines, HEC-1B and EC-023, were treated with inavolisib (supplied by Genentech). Cell proliferation was evaluated by MTT and colony formation assays. Cellular stress was evaluated by measuring levels of reactive oxygen species (ROS) via DCFH-DA assay and change in mitochondrial membrane potential via JC-1 assay. Cell cycle profile was evaluated by Cellometer. Apoptosis was evaluated using cleaved caspace-3 assay. Cell adhesion was evaluated using laminin-1 assay, and cell migration was assessed by wound healing assay. Western immunoblotting (WB) was used to measure downstream protein expression related to cell cycle progression, cellular invasion, and apoptosis. Results: Inavolisib inhibited the cell proliferation and colony formation of HEC-1B and EC-023 cells, in a dose dependent manner (IC50: HEC-1B 7921 nM, EC-023: 310 nM). After 24 hours of treatment, inavolisib induced G1 cell cycle arrest in both cell lines. Treatment with inavolisib increased intracellular ROS levels and reduced mitochondrial membrane potential compared to control groups (all p<0.05). Importantly, inavolisib effectively decreased cell adhesive and migrative abilities in the HEC-1B and EC-023 cell lines (all p<0.05). WB supported these results, showing that treatment with inavolisib resulted in downregulation of the cell cycle regulatory proteins cyclin D-1, CDK2 and CDK4, inhibition of downstream targets of the PIK3CA pathway (phosphorylated [p]-AKT, p-44/42, and p-S6), and upregulation of the pro-apoptotic protein Bcl-xl, Bcl-2, and Mcl-1 in both cell lines. Conclusions: Inavolisib demonstrated potent anti-proliferative and anti-invasive effects in endometrioid EC cell lines. Inavolisib may be a novel treatment strategy in EC, a cancer well-known for alterations in the PIK3CA/mTOR pathway.