Targeting Cyclin Dependent Kinases 4/6 Activity in Pancreatic Ductal Adenocarcinoma
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Pancreatic ductal Adenocarcinoma (PDA) is an aggressive and lethal disease that lacks an adequate treatment. Given that patients with PDA only marginally benefit from the current therapies, there is an urgent need to develop more effective approaches that specifically target PDA. Because a significant portion of PDA tumors lose p16 expression and often over-express Cyclin D1, we hypothesized that CDK4/6 activity is deregulated leading to uncontrolled proliferation. Thus, PDA would represent a good candidate for treatment with recently developed CDK4/6 inhibitors. Our study first investigated the sensitivity of PDA cells to CDK4/6 inhibition and found that PDA cells exhibit variable responses to CDK4/6 inhibition, incling models that display significant resistance. Interestingly, these models showed a novel mechanism of resistance to CDK4/6 inhibition. Prior to this study, RB loss was the only mechanism known to circumvent CDK4/6 inhibition. However, herein, we uncovered that CDK4/6 inhibition can lead to aberrant Cyclin E expression, which can compensate for CDK4/6 activity loss and maintain RB in a hyper-phosphorylated state. Subsequent findings demonstrated that this resistance could be blocked by combination therapy with MTOR inhibitors, which prevented aberrant Cyclin E expression and reinforced RB activation. Our second study found that prolonged CDK4/6 inhibition led to an altered metabolic state with an increased in oxidative respiration and glycolysis accompanied by mitochondria accumulation and increase cellular complexity. This heightened metabolic state was mediated by MTOR signaling, which activity was stimulated by amino acid accumulation and an increase in lysosome production in CDK4/6 treated PDA cells. Lastly, we unveiled new combination therapies that targeted the altered metabolism state of CDK4/6 inhibitor treated cells by impinging on antioxidants such as Hemoxygenase 1 (HO-1) and catalase (CAT), whose expression was enhanced post treatment, or by targeting BCL-2/BCL-XL using ABT-737. Taken together our data demonstrate that targeting PDA with CDK4/6 inhibitors can represent an efficacious route for treatment. Activation of MTOR and perhaps other signaling pathways likely contribute to intrinsic and acquired resistance to CDK4/6. These combined data would support the combined use of CDK4/6 with MTOR inhibitors and other agents for the treatment of pancreatic cancer.