Targeting Activated Akt with GDC-0068, a Novel Selective Akt Inhibitor That Is Efficacious in Multiple Tumor Models

Abstract

Purpose: We describe the preclinical pharmacology and antitumor activity of GDC-0068, a novel highly selective ATP-competitive pan-Akt inhibitor currently in clinical trials for the treatment of human cancers.Experimental Design: The effect of GDC-0068 on Akt signaling was characterized using specific biomarkers of the Akt pathway, and response to GDC-0068 was evaluated in human cancer cell lines and xenograft models with various genetic backgrounds, either as a single agent or in combination with chemotherapeutic agents.Results: GDC-0068 blocked Akt signaling both in cultured human cancer cell lines and in tumor xenograft models as evidenced by dose-dependent decrease in phosphorylation of downstream targets. Inhibition of Akt activity by GDC-0068 resulted in blockade of cell-cycle progression and reduced viability of cancer cell lines. Markers of Akt activation, including high-basal phospho-Akt levels, PTEN loss, and PIK3CA kinase domain mutations, correlate with sensitivity to GDC-0068. Isogenic PTEN knockout also sensitized MCF10A cells to GDC-0068. In multiple tumor xenograft models, oral administration of GDC-0068 resulted in antitumor activity ranging from tumor growth delay to regression. Consistent with the role of Akt in a survival pathway, GDC-0068 also enhanced antitumor activity of classic chemotherapeutic agents.Conclusions: GDC-0068 is a highly selective, orally bioavailable Akt kinase inhibitor that shows pharmacodynamic inhibition of Akt signaling and robust antitumor activity in human cancer cells in vitro and in vivo. Our preclinical data provide a strong mechanistic rationale to evaluate GDC-0068 in cancers with activated Akt signaling.

Dose-Finding Quantitative 18F-FDG PET Imaging Study with the Oral Pan-AKT Inhibitor GSK2141795 in Patients with Gynecologic Malignancies

“…On a genetic level, PIK3CA/PIK3R1 mutations did not obviously segregate with response to GSK2141795 as measured by RECIST or GCIG CA125 criteria; however, RAS/RAF pathway mutations did coincide with lack of response to AKT inhibition (26,27).…”

“…phospho-AKT levels, which presumably result from feedback inhibition after administration of GSK2141795 (26,27).…”

Picking the Point of Inhibition: A Comparative Review of PI3K/AKT/mTOR Pathway Inhibitors

“…Interestingly, catalytic AKT inhibitors (e.g., GDC-0068 and AZD5363) have inhibitory effects in cell lines with AKT1 mutations (E17K) and AKT3 fusions, whereas allosteric inhibitors (e.g., MK-2206) do not (58,59). MK-2206, AZD5363, and GDC-0068 have all demonstrated increased activity in cell lines with PIK3CA or PTEN alterations (60)(61)(62). This may imply that there is a stronger rationale for AKT inhibitors in tumors with PTEN alterations than pan-PI3K inhibitors.…”

Inhibition of Akt Reverses the Acquired Resistance to Sorafenib by Switching Protective Autophagy to Autophagic Cell Death in Hepatocellular Carcinoma

“…3-MA was dissolved in PBS at a concentration of 200 mmol/L by heating to 60 to 70 C immediately before use. For animal experiments, sorafenib was suspended in the vehicle solution containing Cremophor (Sigma-Aldrich), 95% ethanol and water in a ratio of 1:1:6 (22), and GDC0068 was dissolved in 0.5% methylcellulose/0.2% Tween-80 (23). The PI (propidium iodide)/Annexin V-FITC apoptosis detection kit was from BD Biosciences.…”