Novel Dual PI3K/mTOR Inhibitor, Apitolisib (GDC-0980), Inhibits Growth and Induces Apoptosis in Human Glioblastoma Cells

Deregulated PI3K/AKT/mTOR signalling commonly exists in glioblastoma, making this axis an attractive target for therapeutic manipulation. Given that activation of PI3K/AKT/mTOR promotes tumour growth, metastasis, and resistance to anticancer therapies, mTOR inhibitors show promise in the treatment of cancer. The aim of this study was to investigate the underlying mechanism of novel dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in A-172 and U-118-MG GBM tumour cell line suppression. It has been demonstrated that GDC-0980 induces time- and dose-dependent cytotoxicity and apoptosis in investigated glioma cell lines. In our study, the strongest induction of apoptosis was exhibited in the A-172 line after 48 h of incubation with 20 µM GDC-0980, where we observed 46.47% of apoptotic cells. In conclusion, we first discovered that dual PI3K/mTOR blockade by GDC-0980 markedly suppressed survival of human GBM cells and induced apoptosis, independent of the ER stress-mediated DR5 activation. We suggest that GDC-0980, by exerting an inhibitory effect on PERK expression, may thus block its inhibitory effect on protein synthesis, leading to intensification of translation, and this may result in an increase in apoptosis. On the other hand, CHOP stimulates protein synthesis and increases apoptosis. These findings suggest that GDC-0980 may be a candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy.

 

Comments：

The study aimed to investigate the mechanism of action of a dual PI3K/mTOR inhibitor, Apitolisib (GDC-0980), in suppressing the growth of glioblastoma multiforme (GBM) cells. The PI3K/AKT/mTOR signalling pathway is known to be deregulated in GBM, and mTOR inhibitors have shown promise in the treatment of cancer.

The results of the study demonstrated that GDC-0980 induced time- and dose-dependent cytotoxicity and apoptosis in A-172 and U-118-MG GBM cell lines. The strongest induction of apoptosis was observed in the A-172 line after 48 hours of incubation with 20 µM GDC-0980, where 46.47% of apoptotic cells were observed.

The study also suggested that GDC-0980 may block the inhibitory effect of PERK on protein synthesis, leading to an intensification of translation, which may result in an increase in apoptosis. In addition, CHOP was found to stimulate protein synthesis and increase apoptosis.

Overall, the study suggests that GDC-0980 may be a potential candidate for further evaluation as a chemotherapeutic agent for anti-GBM therapy.

Related Products

Cat.No.	Product Name	Information
S2696	Apitolisib (GDC-0980)	Apitolisib (GDC-0980, RG7422, GNE 390) is a potent, class I PI3K inhibitor for PI3Kα/β/δ/γ with IC50 of 5 nM/27 nM/7 nM/14 nM in cell-free assays, respectively. Also a mTOR inhibitor with Ki of 17 nM in a cell-free assay, and highly selective versus other PIKK family kinases. Apitolisib activates autophagy and apoptosis simultaneously in pancreatic cancer cells. Phase 2.

Related Targets

Apoptosis related mTOR Autophagy PI3K