Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and BEZ235 in prostate cancer

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. Prostate cancer remains as the leading cause of cancer-related death for men 1. Most current therapies exhibit issues with significant side effects, therefore it is crucial to develop lower toxicity therapeutics which would reduce the impact of treatment on patients' lives. Overexpression of the PIM family in prostate cancer has been found to lead to increased tumorigenicity and faster progression of the disease due to its impact on metastasis formation, invasion and migration 2-4. Clinically, PIM can lead to decreased overall survival, insensitivity to cancer treatment and increased proliferation 5. Its effect is mainly mediated by interactions with other pathways including PI3K/mTOR (Phosphoinositide 3-kinase; mammalian target of rapamycin), and various downstream effectors 2,6,7. The PI3K/mTOR pathway deregulation in cancer correlates with disease progression 8 and impacts on apoptosis, survival and cell growth 6. The PI3K pathway also regulates multiple oncogenes and tumour suppressor genes 8. Despite being an attractive pathway for anti-cancer drug targeting, results from monotherapeutic PI3K inhibition strategies have been disappointing, with the growing consensus being that improved co-targeting strategies are warranted 9-11 .

Co-Targeting PIM Kinase and PI3K/mTOR in NSCLC

“…Cen et al showed that inhibition of Akt led to transcriptional induction of PIM1 kinase which in turn regulated the expression of RTKs in prostate cancer [5]. We have shown that a co-targeted approach is more effective compared to single PIM kinase or PI3K-mTOR inhibition, as previously reported in prostate cancer [10].…”

Combination Therapy of the Active KRAS-Targeting Antibody inRas37 and a PI3K Inhibitor in Pancreatic Cancer

“…BEZ235 inhibits multiple class I PI3K isoforms and mTORC1/2 kinase activity, exerts potent anticancer activity, and attenuates PI3K reactivation and mTORC2-mediated AKT reactivation (Chiarini et al, 2015). It has exhibited antitumor effects in various cancers, including pancreatic cancer, and its synergistic effects have been revealed in combination with numerous drugs, including cytotoxic drugs and target inhibitors https://doi.org/10.4062/biomolther.2021.145 (Murakami et al, 1987;Zhu et al, 2015;Chen et al, 2018;Luszczak et al, 2020;Ruan et al, 2020). However, PI3K inhibitors, including BEZ-235, have been reported to enhance MEK/ERK pathway activation through a negative feedback loop mediated by mTORC2 in pancreatic cancer cells, leading to drug resistance (Soares et al, 2015).…”

Targeting signaling pathways in prostate cancer: mechanisms and clinical trials

“…The combination of the PIM inhibitor AZD1208 and the PI3K/mTOR inhibitor BEZ235 (dactolisib) has been investigated in clinical trials. 399 A novel and highly efficient triple PIM/PI3K/mTOR inhibitor AUM302 elicited a superior functional outcome compared to the effects of the combination of AZD1208 and BEZ235; these results may help reduce treatment toxicity in future trials. 399 Overall, the clinical application of PI3K/AKT/mTOR inhibitors is still limited in PCa, and further studies that can identify new biomarkers for patient selection or improve co-targeting strategies are still required to enhance their therapeutic effects.…”