Abstract
The phosphoinositide 3-kinase (PI3K) signaling pathway is significantly altered in a wide variety of human cancers, driving cancer cell growth and survival. Consequently, a large number of PI3K inhibitors are now in clinical development. To begin to improve the selection of patients for treatment with PI3K inhibitors and to identify de novo determinants of patient response, we sought to identify and characterize candidate genomic and phosphoproteomic biomarkers predictive of response to the selective PI3K inhibitor, GDC-0941, using the NCI-60 human tumor cell line collection. In this study, sixty diverse tumor cell lines were exposed to GDC-0941 and classified by GI50 value as sensitive or resistant. The most sensitive and resistant cell lines were analyzed for their baseline levels of gene expression and phosphorylation of key signaling nodes. Phosphorylation or activation status of both the PI3K-Akt signaling axis and PARP were correlated with in vitro response to GDC-0941. A gene expression signature associated with in vitro sensitivity to GDC-0941 was also identified. Furthermore, in vitro siRNA-mediated silencing of two genes in this signature, OGT and DDN, validated their role in modulating sensitivity to GDC-0941 in numerous cell lines and begins to provide biological insights into their role as chemosensitizers. These candidate biomarkers will offer useful tools to begin a more thorough understanding of determinants of patient response to PI3K inhibitors and merit exploration in human cancer patients treated with PI3K inhibitors.
Highlights
The phosphoinositide 3-kinase (PI3K) signaling cascade is one of the most frequently de-regulated pathways in human cancer [1], resulting in aberrant cell proliferation and migration
As others previously reported based on analysis of breast cancer cell lines [6], we found an association between PI3KCA mutational status amongst cells in the NCI-60 tumor cell line collection and sensitivity to GDC-0941
We found no association between mutational status of additional effectors in the PI3K-signaling pathway (AKT1, PDK1, MTOR) amongst cells in the NCI-60 tumor cell line collection and sensitivity to GDC-0941
Summary
The PI3K (phosphoinositide 3-kinase) signaling cascade is one of the most frequently de-regulated pathways in human cancer [1], resulting in aberrant cell proliferation and migration. Activation by upstream receptor tyrosine kinases stimulates PI3K-mediated conversion of phosphatidylinositol (4,5) diphosphate (PIP2) into the secondary messenger phosphatidylinositol (3,4,5) triphosphate (PIP3). PIP3 subsequently recruits 3-phosphoinositide dependent protein kinase 1 (Pdpk1) and the serine-threonine protein kinase Akt to the plasma membrane, culminating in the phosphorylation and activation of Akt. PIP3 subsequently recruits 3-phosphoinositide dependent protein kinase 1 (Pdpk1) and the serine-threonine protein kinase Akt to the plasma membrane, culminating in the phosphorylation and activation of Akt It is Akt which mediates a cascade of phosphorylation events leading to the activation of downstream pathways promoting tumor survival and growth [1,2]. Additional mutations include amplifications and activating mutations in PI3KCB, PDPK1 and AKT1 and loss of heterozygosity and mutational inactivation of PTEN, a negative regulator of PI3Ksignaling [1,2,3]
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