Back to results

The impact of mutations in PI3K/AKT pathway gene loci on response to PI3K inhibitors

Background: PIK3CA mutations in breast cancer (BC) lead to aberrrant activation of the PI3K/AKT-pathway, however, they have not proven to be a good predictor of patient response in clinical trials of PI3K inhibitors. Therefore, suggesting the PI3K/AKT-pathway is activated by additional mechanisms in many BCs. We hypothesise that both coding and non-coding ‘regulatory’ mutations in the gene loci of members of the PI3K/AKT-pathway, influence how BCs respond to PI3K inhibitors. To test our hypothesis, we have been granted access to a biobank of 300 BC patient tumour samples, we will undertake the following: Objective 1:To identify novel coding and non-coding mutations in the gene loci of members of the PI3K/AKT-pathway. Objective 2:To functionally evaluate the oncogenic potential of coding and noncoding mutations which affect the activity of the PI3K/AKT-pathway. Objective 3:To determine the most synergistic combinations of PI3K inhibitors and specific targeted therapies to best treat a cohort of BC patients with PI3K/AKTpathway mutated cancer. Methods: We will use targeted DNA sequencing of patient tumours to identify mutations occurring in the extended gene loci of 32 members of the PI3K/AKTpathway. We will perform functional assays to evaluate if the mutations result in deregulation of the PI3K/AKT-pathway using CRISPR generated isogenic BC cell lines. We will determine if mutations increase activity of PI3K/AKT-pathway signalling and identify both in vitro and in vivo the best single or combinations of PI3K inhibitors and targeted drugs to treat these BCs. Impact on breast cancer: At the end of this project we will have identified the most oncogenic mutations affecting the PI3K/AKT-pathway and discovered the most synergistic combination of drugs that can be used to effectively treat breast cancers with these mutations.