Predictive Biomarkers of Sensitivity to the Phosphatidylinositol 3′ Kinase Inhibitor GDC-0941 in Breast Cancer Preclinical Models

Abstract

Purpose: The class I phosphatidylinositol 3′ kinase (PI3K) plays a major role in proliferation and survival in a wide variety of human cancers. A key factor in successful development of drugs targeting this pathway is likely to be the identification of responsive patient populations with predictive diagnostic biomarkers. This study sought to identify candidate biomarkers of response to the selective PI3K inhibitor GDC-0941.Experimental Design: We used a large panel of breast cancer cell lines and in vivo xenograft models to identify candidate predictive biomarkers for a selective inhibitor of class I PI3K that is currently in clinical development. The approach involved pharmacogenomic profiling as well as analysis of gene expression data sets from cells profiled at baseline or after GDC-0941 treatment.Results: We found that models harboring mutations in PIK3CA, amplification of human epidermal growth factor receptor 2, or dual alterations in two pathway components were exquisitely sensitive to the antitumor effects of GDC-0941. We found that several models that do not harbor these alterations also showed sensitivity, suggesting a need for additional diagnostic markers. Gene expression studies identified a collection of genes whose expression was associated with in vitro sensitivity to GDC-0941, and expression of a subset of these genes was found to be intimately linked to signaling through the pathway.Conclusion: Pathway focused biomarkers and the gene expression signature described in this study may have utility in the identification of patients likely to benefit from therapy with a selective PI3K inhibitor. Clin Cancer Res; 16(14); 3670-83. ©2010 AACR.The PIK3CA gene encodes the p110α catalytic subunit of class I phosphatidylinositol 3′ kinase (PI3K) and is mutated or amplified with high frequency in several solid tumor malignancies (1-3). The mutant versions of the protein exhibit increased enzymatic activity independent of upstream signaling, constitutively stimulates signaling through the AKT pathway, and has oncogenic properties such as conferring anchorage-independent growth and increased cell invasion and metastasis (4). Structural analyses have revealed that oncogenic mutations in p110α often lie at the interface between p110 and the p85 regulatory subunit, or between the kinase domain of p110 and other domains within the catalytic subunit, suggesting that they may disrupt the regulation of kinase activity by p85 or increase the catalytic activity of the enzyme, respectively (5, 6). Other key nodes of the PI3K signaling pathway are also frequently deregulated in a wide variety of cancers, including receptor tyrosine kinases that stimulate PI3K activity [e.g., human epidermal growth factor receptor 2 (HER2); ref. 7], the downstream effector kinase AKT1 (8), and the negative regulator PTEN (9). This frequent activation of the PI3K pathway in cancers has led to intensive efforts to identify therapeutics that abrogate PI3K signaling and hence may have utility in patients with cancers addicted to the...

PI3K Inhibitors Synergize with FGFR Inhibitors to Enhance Antitumor Responses in FGFR2mutant Endometrial Cancers

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