The phosphoinositide 3-kinase (PI3K) signalling pathway is activated in a broad spectrum of human cancer. Activation of this pathway often occurs indirectly by the activation of receptor tyrosine kinases, or directly by mutations in PI3K genes, such as PIK3CA. GSK1059615 is a novel, ATP-competitive small molecule reversible inhibitor of the class I family of PI3K. GSK1059615 equally inhibits the wild-type enzyme (WT) compared to the 3 ‘hotspot’ mutants of PI3Kα. This inhibition of enzyme activity translates effectively to activity in cellular assays.
 As part of an effort to characterize markers of response to GSK1059615, 289 tumor derived cell lines of mixed histology were assayed for sensitivity using a 3-day proliferation assay as well as for DNA copy number alterations and base line transcriptomics using microarray-based techniques. Using gIC50 values, breast, kidney, and ovarian cell lines emerged as more sensitive tumor types, while pancreas and lung appeared less sensitive. Molecular analyses of the most sensitive and least sensitive breast lines indicates that activating mutations of PIK3CA are associated with increased sensitivity, where 6/11 (55%) of the most sensitive lines harbor a mutation while 2/11 (18%) occurred in the least sensitive group. Furthermore, genome-wide transcript profiles suggest the luminal subtype of breast tumors as a potential clinical target for GSK1059615.
 GSK1059615 has an attractive biological profile and has entered Phase 1 human clinical trials. Furthermore, modelling positive predictors, such as PIK3CA mutations in breast cancer can reduce the size of a clinical registration trial for GSK1059615 by approximately 25%.

Third AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development-- Sep 22-25, 2008; Philadelphia, PA