1. ErbB activation and heterodimerisation is responsible for resistance upon PI3K-mTOR inhibition in metastatic prostate cancer
- Author
-
Galazi, Myria
- Subjects
616.99 - Abstract
My hypothesis is that resistance to PI3K-AKT-mTOR targeting in metastatic prostate cancer involves ErbB activation and heterodimerisation. Better description of the mechanisms implicated will allow the identification of appropriate predictive biomarkers. Current clinical trials are investigating the use of PI3K-AKT-mTOR inhibitors in metastatic castration-resistant prostate cancer (CRPC). 50-70% of metastatic CRPC patients have genomic aberrations of the PI3K pathway, mainly involving loss of PTEN, an important negative regulator of the PI3K-AKT pathway. Upregulation of HER3 was previously suggested to be an important resistance mechanism. Within the context of this project I have applied biophysical techniques to quantify protein-protein interactions i.e fluorescence lifetime imaging microscopy (FLIM) which is the gold-standard technique for measuring Forster resonance energy transfer (FRET). This is an established technology in our laboratory and was used to evaluate HER3 heterodimerisation in prostate cancer cells and mouse xenograft tissue, alongside biochemical methods to demonstrate changes in ErbB expression in response to PI3K-AKT-mTOR inhibition. In addition, I optimised this technology for use in cell line and patientderived exosomes. Different ErbB subtypes are upregulated in vitro as part of a potential resistance mechanism in response to PI3K-mTOR inhibition, depending on the cell line PTEN status. Concomitant upregulation of either AR or PSMA is also observed. In PTEN WT prostate cancer cells, the upregulation of PSMA is demonstrated to be HER2 dependent and can be inhibited by lapatinib. The clinical implications of my results propose the use of PI3K-AKT-mTOR inhibitors in the metastatic hormone-sensitive setting as well. In addition, tissue and/or exosomal ErbB heterodimerisation, together with the use of clinically available PSMA imaging probes, might prove an additional biomarker in resistance detection and subgroup classification. Some initial PSMA PET imaging analyses upon PI3K-mTOR inhibition in vivo will be presented. Finally, this might allow the design of prospective clinical trials using PSMA-targeted therapies.
- Published
- 2020