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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.

Intrinsic or acquired resistance to chemotherapeutic agents is a common phenomenon and a major challenge to the treatment of cancer patients, especially those with progressive disease. Chemoresistance is defined by a complex network of factors including multi-drug resistance proteins, reduced cellular uptake of the drug, enhanced DNA repair, intracellular drug inactivation and evasion of apoptosis. Preclinical models have demonstrated activation of the NF-κB pathway by several chemotherapy drugs, including platinum based agents, anthracyclines and taxanes. NF-κB is a key transcription factor, playing a role in the development and progression of cancer as well as chemoresistance through the activation of anti-apoptotic genes. Consequently, NF-κB has emerged as a promising anticancer target. Here, we describe the role of NF-κB in the cancer cell and in resistance to chemotherapeutic agents, particularly cisplatin. Additionally, the potential benefits and disadvantages of targeting NF-κB signalling by pharmacological intervention will be addressed.