1. Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer
- Author
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Sabina Luszczak, Benjamin S. Simpson, Urszula Stopka-Farooqui, Vignesh Krishna Sathyadevan, Lina M. Carmona Echeverria, Christopher Kumar, Helena Costa, Aiman Haider, Alex Freeman, Charles Jameson, Marzena Ratynska, Imen Ben-Salha, Ashwin Sridhar, Greg Shaw, John D. Kelly, Hayley Pye, Kathy A. Gately, Hayley C. Whitaker, and Susan Heavey
- Subjects
Medicine ,Science - Abstract
Abstract 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 effectors 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 efficacy. 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 offered 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.
- Published
- 2020
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