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

• Published in: Clinical cancer research 2010-07, Vol.16 (14), p.3670-3683
• Main Authors: O'BRIEN, Carol, WALLIN, Jeffrey J, BEIVIN, Marcia, FRIEDMAN, Lori S, LACKNER, Mark R, SAMPATH, Deepak, GUHATHAKURTA, Debraj, SAVAGE, Heidi, PUNNOOSE, Elizabeth A, GUAN, Jane, BERRY, Leanne, PRIOR, Wei Wei, AMLER, Lukas C
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Biomarkers, Tumor - antagonists & inhibitors; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Breast Neoplasms - drug therapy; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Cell Cycle - drug effects; Cell Line, Tumor; Cell Survival - drug effects; Disease Models, Animal; Female; Gene Expression Profiling; Gynecology. Andrology. Obstetrics; Humans; Indazoles - pharmacology; Mammary gland diseases; Mammary Neoplasms, Experimental - drug therapy; Mammary Neoplasms, Experimental - genetics; Mammary Neoplasms, Experimental - metabolism; Medical sciences; Mice; Mutation; Neoplasm Transplantation; Oligonucleotide Array Sequence Analysis; Pharmacology. Drug treatments; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - genetics; Phosphatidylinositol 3-Kinase - metabolism; Predictive Value of Tests; Receptor, ErbB-2 - antagonists & inhibitors; Receptor, ErbB-2 - genetics; Sensitivity and Specificity; Sulfonamides - pharmacology; Tumors; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-09-2828

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. 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. 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. 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.