Abstract A281: Exploratory study on predictive biomarkers for ARQ 092, a novel selective pan-AKT inhibitor.
Authors: Yu Yi , Carazza Rebecca , Chen Chang-Rung , Isoyama Takeshi , Tazaki Koichi , Fujiwara Kosaku , Dransfield Daniel T. 
Published: August 2014

Background: AKT is a serine/threonine kinase and a critical component mediating PI3K-AKT signaling axis. It plays an important role in cell cycle progression, survival, proliferation and growth. Hyperactivation of PI3K-AKT signaling pathway has been described as a key driver in cancer initiation and progression. Targeting this pathway has become a novel strategy against cancer. AKT can be constitutively activated through activated receptor tyrosine kinases, gain-of-function mutations of PIK3CA, or inactivation of PTEN, and its amplification or over-expression. As a tumor suppressor, E-cadherin encoded by CDH1 gene and its loss promotes Epithelial-Mesenchymal Transition and metastasis, for which PI3K-AKT signaling is required. ARQ 092 is a non ATP competitive and selective pan-AKT inhibitor with IC50 of 2.3 nM, 9.3 nM and 17 nM for AKT1, 2, and 3 respectively.

Methods: Cellular and tumor pharmarcodynamic studies were performed in AN3-CA cells using western blot analysis and IHC. Anefficacy study of ARQ 092 was performed in a mouse xenograft model using the Her2+ KPL-4 breast cancer cell line. Broad anti-proliferative effects of ARQ 092 were assessed using the Oncopanel profiling analysis on the growth of 240 human cancer cell lines. Somatic mutations for each cell line were obtained from the COSMIC database and correlation between somatic mutations and ARQ 092 sensitivity was assessed.

Results: ARQ 092 inhibits phospho AKT (pAKT) and its downstream phospho PRAS40 (pPRAS40) in AN3-CA cells with IC50 of 62 nM for pAKT(T308), 40 nM for pAKT(S473), and 312 nM for pPRAS40(T246). Significant inhibition of pAKT and pPRAS40 were also observed in AN3-CA tumor xenograft model. In an in vivo efficacy study with KPL-4 cell-derived xenograft model, ARQ 092 suppresses tumor growth at doses (20 and 40 mg/kg), and caused tumor regression at higher doses (80 and 120 mg/kg). Oncopanel profile analysis showed that breast and kidney are the top two cancer types sensitive to ARQ 092. Approximately 65% (11/17) of breast cancer cells and 40% (4/10) kidney cancer cells have GI50 of less than 1 μM. Somatic mutation analysis from the combined group of sensitive (GI50&lt;1 μM) and resistant (GI50&gt;4 μM) cell lines revealed that 87% (20/23) cancer cell lines contain PIK3CA mutations and were sensitive to ARQ 092 (GI50&lt;1μM); and among those cells, 30% (7/23) are breast cancer cells. Furthermore, we have identified loss-of-function mutation of CDH1 gene coding E-cadherin is associated with ARQ 092 sensitivity in four cell lines. Among those four cell lines, three are breast cancer cell lines.

Conclusions: ARQ 092 has exhibited potent anti-proliferative effects on a large panel of cancer cell lines, particularly breast and kidney cancer cells. Mutation analysis indicates that gain-of-function of PIK3CA or loss-of-function of CDH1 predicts ARQ 092 sensitivity which could bepredictive biomarkers for patient stratification. Our analysis also suggests that breast cancer patients may represent a targeted indication for ARQ 092.

Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A281.

Citation Format: Yi Yu, Rebecca Carazza, Chang-Rung Chen, Takeshi Isoyama, Koichi Tazaki, Kosaku Fujiwara, Daniel T. Dransfield. Exploratory study on predictive biomarkers for ARQ 092, a novel selective pan-AKT inhibitor. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A281.