Elucidating resistance to AKT inhibition in metastatic breast cancer
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Embargo End Date
2030-04-11
ICR Authors
Authors
Mearns, S
Document Type
Thesis or Dissertation
Date
2025-04-11
Date Accepted
Abstract
Targeted therapies have generated promising results both pre-clinically and clinically, but resistance remains an inevitable issue especially in the treatment of advanced cancer. The PI3K-AKT pathway is frequently altered in cancer, including breast, and capivasertib (AKT inhibitor) has shown promising clinical trial results with FDA approval (2023). However, acquired resistance mechanisms remain undocumented, especially AKT1 activating mutations due to the lack of AKT1 E17K mutant breast cancer models. By understanding mechanisms of acquired resistance, the hope is to identify novel therapeutic strategies.
To investigate this new AKT1 E17K models were developed, both patient derived organoids (PDOs) from AKT1 E17K breast cancer patients’ tumours, as well as CRISPR-Cas9 edited cancer cell lines. Mutant models were characterised and resistance to capivasertib generated. To assess in vivo effects of capivasertib in the PDO model, a xenograft experiment was conducted.
Derived resistant cell lines maintained AKT inhibition under capivasertib exposure, shown by inhibited phosphorylation of downstream markers and Foxo3a nuclear localisation. Resistant cells showed upregulated oestrogen and mTOR signalling, plus reengagement of translation. An siRNA screen was used to investigate potential sensitisers, and drug combinations targeting the resistance phenotype identified. Proteomics showed increased FOXP1 in the resistant cells, which has been shown to be an oestrogen signalling output and able to suppress Foxo3a induced apoptosis, this will be explored in future work.
To extend the pre-clinical work, a cohort of AKT1 mutant breast cancers was collated from three trials/ studies, and sequencing (RNA and WES) was used to identify de novo determinants of response to capivasertib. Patients with allelic imbalance (LOH of the WT allele or mutant amplification) had significantly greater PFS benefit on capivasertib and was prognostic/predictive.
Citation
2025
DOI
Source Title
Publisher
Institute of Cancer Research (University Of London)
ISSN
eISSN
Collections
Research Team
Molecular Oncology