Article | Open Access | Published:
Molecular Diagnostics
Functional activation of the AKT-mTOR signalling axis in a real-world metastatic breast cancer cohort
Deepika Prasad, Elisa Baldelli, Edik M. Blais, Justin Davis, Emna El Gazzah, Claudius Mueller, Alison Gomeiz, Aisha Ibrahim, Avani Vinayak Newrekar, Brian A. Corgiat, Rick Dunetz, Emanuel F. Petricoin III, Qi Wei and Mariaelena Pierobon © The Author(s) 2024
Abstract
BACKGROUND:
Mutations of the PIK3CA/AKT/mTOR axis are common events in metastatic breast cancers (MBCs). This study was designed to evaluate the extent to which genetic alterations of the PIK3CA/AKT/mTOR can predict protein activation of this signalling axis in MBCs.
METHODS:
Molecular profiles were generated by CLIA-certified laboratories from a real-world evidence cohort of 171 MBC patients. Genetic alterations of the PIK3CA pathway were measured using next-generation sequencing. Activation levels of AKT and downstream signalling molecules were quantified using two orthogonal proteomic methods. Protein activity was correlated with underlying genomic profiles and response to CDK4/6 inhibition in combination with endocrine treatment (ET).
RESULTS:
Oncogenic alterations of the PIK3CA/AKT/PTEN pathway were identified in 49.7% of cases. Genomic profiles emerged as poor predictors of protein activity (AUC:0.69), and AKT phosphorylation levels mimicked those of mutant lesions in 76.9% of wildtype tumours. High phosphorylation levels of the PI3K/AKT/mTOR downstream target p70S6 Kinase (T389) were associated with shorter PFS in patients treated with CDK4/6 inhibitors in combination with ET (HR:4.18 95%CI:1.19–14.63); this association was not seen when patients were classified by mutational status.
CONCLUSIONS:
Phosphoprotein-based measurements of drug targets and downstream substrates should be captured along with genomic information to identify MBCs driven by the PI3K/AKT/mTOR signalling.
British Journal of Cancer (2024) 131:1543–1554; https://doi.org/10.1038/s41416-024-02852-y