The following review discusses the trend of PDAC therapy towards molecular subtyping for biomarker-driven personalised therapies, highlighting the key pathways under investigation and their relationship to the PI3K pathway.
Here, we demonstrate that combining the dual PI3K/mTOR inhibitor PF5212384 (PF384) and MEK inhibitor PD325901 (PD901) more effectively induces apoptosis compared with either agent alone, independent of KRAS mutational status in PDAC cell lines.
Subnetworks that were associated with apoptosis or proliferation were extracted from the 17 pathways and a new network was constructed using Cytoscape software, which identified that mitogen-activated protein kinase, PI3K/AKT and WNT/β-catenin signaling pathways may be associated with PDAC development.
Recent evidence suggests that phosphoinositide 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase 1 (PDK1) are key effectors of oncogenic KRAS in PDAC.
These findings suggest that the standard chemotherapy response of PDAC can be enhanced through dual targeting of PI3K and MAPK signaling, which could lead to improved PDAC therapy.
Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth <i>in vitro</i> and <i>in vivo</i> Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients.<i></i>.
Phosphoglycerate Mutase 1 (PGAM1) Promotes Pancreatic Ductal Adenocarcinoma (PDAC) Metastasis by Acting as a Novel Downstream Target of the PI3K/Akt/mTOR Pathway.
Finally, an activator (740Y-P) and inhibitor (LY294002) of the PI3K/AKT signaling pathway were used in the western blot assays and the following rescue experiments, demonstrating that SNHG1 facilitates cell proliferation and tumorigenicity partly via the PI3K/AKT signaling pathway in PDAC.
Here, we assess resistance to therapeutic inhibition of the PI3K pathway within the hypoxic microenvironment of pancreatic ductal adenocarcinoma (PDAC) and identify a phenomenon whereby pronounced hypoxia-induced resistance is observed for three clinically relevant inhibitors.
More than 90% of PDAC tumors harbor driver mutations in <i>K-Ras</i> that activate various downstream effector-signaling pathways, including the phosphoinositide-3-kinase (PI3K) pathway.
Our study validated HIF-2α was an important factor in PDAC progression and poor prognosis and may promote non-canonical glutamine metabolism via activation of PI3K/mTORC2 pathway.
To determine the regulation and function of the neural precursor cell expressed developmentally down regulated protein 4 (NEDD4) in PDAC and to determine its dependency on phosphatase and tensin homolog (PTEN) and PI3K/AKT signaling.
In this review, we focus on the progress in the development of Akt, PI3K and mTOR inhibitors for clinical applications, together with the need for the development of in PDAC and the need for the identification of predictive biomarkers and combination strategies with less toxicity in counteracting the mechanisms of resistance to the therapy.
These data indicate the central role that macrophage PI3Kγ plays in PDAC progression and demonstrate that pharmacologic inhibition of PI3Kγ represents a new therapeutic modality for this devastating tumor type.
We have recently shown that Cyr61 promotes growth of pancreatic ductal adenocarcinoma (PDAC) through PI3k/Akt signaling-enhanced nuclear exclusion of p27.
Treatment of PDAC-bearing mice with the BTK inhibitor PCI32765 (ibrutinib) or by PI3Kγ inhibition reprogrammed macrophages toward a T(H)1 phenotype that fostered CD8(+) T-cell cytotoxicity, and suppressed PDAC growth, indicating that BTK signaling mediates PDAC immunosuppression.
We further demonstrate that inhibition of KRAS signaling alone via co-targeting the MAPK and PI3K pathways fails to induce extensive tumor cell death and, therefore, has limited efficacy against PDAC.
Here, we demonstrate that treatment of PANC-1 or MiaPaCa-2 pancreatic ductal adenocarcinoma (PDAC) cells with the dual PI3K/mTOR kinase inhibitor (PI3K/TOR-KI) BEZ235 blocked mTORC1/S6K activation (scored by S6 phosphorylation at Ser(240/244)), mTORC1/4E-BP1 (assayed by 4E-BP1 phosphorylation at Thr(37/46)), and mTORC2-mediated AKT phosphorylation at Ser(473), in a concentration-dependent manner.