| Title: |
Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer |
| Authors: |
Luszczak, S; Simpson, BS; Stopka-Farooqui, U; Sathyadevan, VK; Echeverria, LMC; Kumar, C; Costa, H; Haider, A; Freeman, A; Jameson, C; Ratynska, M; Ben-Salha, I; Sridhar, A; Shaw, G; Kelly, JD; Pye, H; Gately, KA; Whitaker, HC; Heavey, S |
| Source: |
Scientific Reports , 10 , Article 14380. (2020) |
| Publication Year: |
2020 |
| Collection: |
University College London: UCL Discovery |
| Description: |
PIM and PI3K/mTOR pathways are often dysregulated in prostate cancer, and may lead to decreased survival, increased metastasis and invasion. The pathways are heavily interconnected and act on a variety of common efectors that can lead to the development of resistance to drug inhibitors. Most current treatments exhibit issues with toxicity and resistance. We investigated the novel multikinase PIM/PI3K/mTOR inhibitor, AUM302, versus a combination of the PIM inhibitor, AZD-1208, and the PI3K/mTOR inhibitor BEZ235 (Dactolisib) to determine their impact on mRNA and phosphoprotein expression, as well as their functional efcacy. We have determined that around 20% of prostate cancer patients overexpress the direct targets of these drugs, and this cohort are more likely to have a high Gleason grade tumour (≥Gleason 8). A co-targeted inhibition approach ofered broader inhibition of genes and phosphoproteins in the PI3K/mTOR pathway, when compared to single kinase inhibition. The preclinical inhibitor AUM302, used at a lower dose, elicited a comparable or superior functional outcome compared with combined AZD-1208 +BEZ235, which have been investigated in clinical trials, and could help to reduce treatment toxicity in future trials. We believe that a co-targeting approach is a viable therapeutic strategy that should be developed further in pre-clinical studies. |
| Document Type: |
article in journal/newspaper |
| File Description: |
text |
| Language: |
English |
| Relation: |
https://discovery.ucl.ac.uk/id/eprint/10108974/1/Sabina%20PIM%20published%20pdf.pdf; https://discovery.ucl.ac.uk/id/eprint/10108974/ |
| Availability: |
https://discovery.ucl.ac.uk/id/eprint/10108974/1/Sabina%20PIM%20published%20pdf.pdf; https://discovery.ucl.ac.uk/id/eprint/10108974/ |
| Rights: |
open |
| Accession Number: |
edsbas.17C825B0 |
| Database: |
BASE |