Abstract
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. 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. 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. 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.
Highlights
The serine/threonine kinase Akt (a.k.a. protein kinase B or PKB) is encoded by 3 closely related genes in humans, Akt1 (PKB-a), Akt2 (PKB-b), and Akt3 (PKB-g), that belong to the AGC family of kinases and share high homology with protein kinase A (PKA) and PKC
Akt is the central node of the PI3K–Akt–mTOR pathway and is negatively regulated by the tumor suppressor PTEN, a phospholipid phosphatase that counteracts the activity of phosphoinositide 3kinase (PI3K)
GDC-0068 is an ATP-competitive inhibitor of Akt (Supplementary Fig. S1; ref. 26) and is equipotent against all 3 Akt isoforms, which share more than 95% sequence identity within the ATP-binding pocket, with potencies ranging from 5 to 18 nmol/L (Supplementary Table S1)
Summary
The serine/threonine kinase Akt (a.k.a. protein kinase B or PKB) is encoded by 3 closely related genes in humans, Akt (PKB-a), Akt (PKB-b), and Akt (PKB-g), that belong to the AGC family of kinases and share high homology with protein kinase A (PKA) and PKC. Akt is the central node of the PI3K–Akt–mTOR pathway and is negatively regulated by the tumor suppressor PTEN, a phospholipid phosphatase that counteracts the activity of phosphoinositide 3kinase (PI3K). The products of PI3K activity, the lipid. Authors' Affiliations: 1Genentech, South San Francisco, California; and 2Array BioPharma Inc., Boulder, Colorado. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). M.A. Nannini contributed to this work and are joint first authors
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