PF-04691502

Upregulation of glucose metabolism via phosphorylation of S6 ribosomal protein appeared to play a role in tumor progression in dCCA. mTORC1 may be a therapeutic target for dCCA.

Our study reveals the potential therapeutic role of dual inhibition of CDK4/6 and PI3K/mTOR pathways in iCCA, and proposes a new paradigm for the clinical treatment of iCCA.

In addition, PF-04691502 increased the apoptosis induced by various chemotherapeutic agents in BC cells. Taken together, PF-04691502 could be used alone or in combination with other chemotherapeutic agents in the treatment of BC.

PIK3R3 plays a pivotal role in ovarian cancer development and is therefore a potential candidate for developing novel therapeutic approaches.

Here, we report on the preclinical activity of the combination of the FLT3 inhibitor quizartinib with the dual PI3K/mTOR inhibitor PF-04691502 in FLT3-ITD cells. Briefly, we show that the association of these two molecules displays synergistic cytotoxicity in vitro in FLT3-ITD AML cells, triggering 90% cell death at nanomolar concentrations after 48 h.

35 CD138-purified MM samples were taken from patients with newly diagnosed or relapsed MM and exposed to therapeutic agents from five therapeutic drug classes including Bortezomib, Quizinostat, Lenalidomide, Navitoclax and PF-04691502. Using Receiver Operating Characteristic curve analysis, strong predictive power for the specificity and sensitivity of these potential biomarkers was identified. This approach has the potential to yield predictive theranostic protein panels that can inform therapeutic decision making.

Treatment with PF-04691502, a dual PI3K/mTOR inhibitor, hampered the increased cell growth and glycolysis due to ARHGAP25 knockdown in PAAD cells. Altogether, these results conclude that ARHGAP25 acts as a tumor suppressor by inhibiting the AKT/mTOR signaling pathway, which might provide a therapeutic target for PAAD.

PF-04691502, a selective PI3K inhibitor, suppressed the augmented phosphorylation of Akt and its substrate FoxO3a. Treatment with afuresertib (a specific Akt inhibitor) in combination with bortezomib additively decreased FAM46C MM cell survival. Collectively, this study is the first to demonstrate that loss of FAM46C triggers the concomitant activation of PI3K-Akt signaling pathway, which might be a therapeutic target for MM with abnormalities in FAM46C gene.

The mammalian Target of Rapamycin (mTOR) and phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway has a well-established role in NETs that was supported by the clinical efficacy, shown by the rapamycin analog, Everolimus.  Our results demonstrate that both PF-04691502 and PKI-402 have a cytostatic inhibitory effect on proliferation in both BON and QGP-1 cells. In addition, treatment with PF-04691502 causes cytotoxic induction of apoptosis in QGP-1 cells, but not in BON cells. Our results suggest that PI3K/mTOR inhibition with PF-04691502 could be a novel therapeutic approach to the treatment of NETs.

P2, N=67, Terminated, Pfizer