The PI3K/AKT pathway is activated downstream of a variety of extracellular signals and activation of this signalling pathway impacts a number of cellular processes including cell growth, proliferation and survival. The 3 AKT isoforms are overexpressed and/or amplified in a range of tumour types making them a target for therapeutic intervention. In addition the pathway is activated through mutations, amplification and overexpression of upstream activators such as PIK3CA, EGFR and ERBB2 and loss of the negative regulator PTEN.
GSK690693 is a potent, low nanomolar pan-AKT kinase inhibitor that inhibits proliferation and induces apoptosis in tumour cells in culture and xenographs. The downstream phosphorylation of GSK3β is inhibited by GSK690693 in a dose and time-dependent manner. Predictive biomarkers that inform treatment choice are of critical importance in the development and application of GSK690693. Proliferation in the presence of GSK690693 was assessed for >350 cancer cell lines to determine tumour types that are more sensitive to this inhibitor. In addition, genome wide copy number data (Affymetrix 500K SNP arrays), expression data (Affymetrix U133+2 arrays) and DNA sequence data from key AKT pathway genes and other genes that might impact on the response of cell lines to GSK690693 was generated. This genomic and genetic data has been analysed with the proliferation data to identify predictive biomarkers.
21 of 42 breast cancer cell lines were sensitive to GSK690693 of which 15 have mutations in either PIK3CA or PTEN that were identical to previously reported somatic mutations in primary cancers. Twelve of these were sensitive to GSK690693 (positive predictive value = 80%). Conversely, 17 breast cell lines had no detectable mutation in either PIK3CA or PTEN of which only 4 were sensitive to GSK690693 (negative predictive value = 76%). In contrast, colon cancer cell lines harbouring mutations in PIK3CA or PTEN were found to be less sensitive to GSK690693. These colon cancer cell lines, however also contained activating mutations in RAS/RAF genes suggesting that mutations in RAS/RAF genes are negative predictors of response to GSK690693 even in the presence of PIK3CA/PTEN mutations in colon cancer cells. Furthermore, cell lines from tumour types with higher frequencies of RAS/RAF mutations such as pancreatic cancer and melanoma were found to be less sensitive to GSK690693. This analysis has identified a series of plausible predictive biomarkers.
- American Association for Cancer Research