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

TLDR

The class I phosphatidylinositol 3′ kinase (PI3K) drives proliferation and survival in many human cancers, and identifying responsive patient populations with predictive diagnostic biomarkers is essential for developing drugs targeting this pathway. This study sought to identify candidate biomarkers of response to the selective PI3K inhibitor GDC‑0941. Using a large panel of breast cancer cell lines and in vivo xenograft models, the authors performed pharmacogenomic profiling and gene expression analyses at baseline and after GDC‑0941 treatment to discover predictive biomarkers. Models harboring PIK3CA mutations, HER2 amplification, or dual pathway alterations were highly sensitive to GDC‑0941, while additional sensitive models lacking these changes highlighted the need for further diagnostic markers; a gene expression signature linked to pathway signaling was also identified. ©2010 AACR; Clin Cancer Res 16(14):3670–83.

Abstract

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.