Lung cancer cells that have become resistant to existing drugs can still be killed by disabling a single enzyme called USP17. This matters because non-small cell lung cancer (NSCLC)—the most common form of lung cancer—often develops resistance to current targeted therapies. Patients whose tumours are driven by mutations in the epidermal growth factor receptor initially respond to inhibitors, but the tumours quickly acquire additional mutations that make those drugs useless. USP17 is highly active in NSCLC cells but absent from healthy lung tissue, and patients with high USP17 levels respond poorly to treatment and are more likely to have metastatic disease. Depleting USP17 not only stops tumour growth but actively triggers cell death, even in cells that have become resistant to existing drugs. The problem is that no specific inhibitor of USP17 exists. This project will screen the AstraZeneca compound library to find molecules that block USP17 selectively. If successful, the identified compounds will serve both as tools to validate USP17 as a drug target and as starting points for developing a new class of NSCLC treatments—potentially offering an option for patients who have run out of effective therapies.
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Lung cancer is the most common cancer worldwide and accounts for nearly 20% of cancer related deaths. Non-small cell lung cancer (NSCLC) is the most predominant form of lung cancer, and these tumours are often driven by mutations of epidermal growth factor receptor. Patients whose tumours are driven by mutations of this receptor have successfully been treated with inhibitors which block its activity. However, these tumours quickly develop resistance to the inhibitors via additional mutations. Therefore, different drug targets are still being sought to treat NSCLC patients with epidermal growth factor receptor mutations, as well as those which have become resistant. USP17 is an enzyme that removes ubiquitin from proteins onto which it has been attached. The addition of ubiquitin can impact the activation, location, or degradation, of proteins and so its removal can also regulate these processes. USP17 is highly expressed in NSCLC, but is not detected in non-malignant lung tissue. Patients with higher levels of USP17 respond poorly to treatment and are more likely to have a tumour that spreads throughout the body. Depleting USP17 in cells derived from NSCLC tumours blocks their growth and migration, which indicates USP17 is a promising target in NSCLC. In addition, we have shown in NSCLC cells derived from tumours with epidermal growth factor receptor mutations, not only does it stop their growth, it also actively leads to cell death. This indicates it represents a particularly interesting target for tumours with these mutations. Indeed, we have also shown USP17 depletion can trigger cell death in cells derived from tumours which have developed resistance to inhibitors of epidermal growth factor receptor. This indicates targeting USP17 could potentially improve the treatment of NSCLC tumours with epidermal growth factor receptor mutations and either treat, or prevent the emergence of, drug resistant cells. However, without a specific inhibitor of USP17, it is difficult to further validate the impact of USP17 inhibition in NSCLC models, and to date there are no reported USP17 specific inhibitors available. Therefore, to allow further validation, and to act as a starting point for drug development, we need to identify compounds which specifically inhibit USP17. As a result, this project aims to identify potential USP17 inhibitors from the AstraZeneca compound library by screening for active and selective inhibitors. Any inhibitors identified can then be used to help further validate USP17 as a target, as well as acting as a starting point for future drug development. Eventually the aim would be to further develop any identified inhibitors to make them suitable for use in the clinic and to provide the basis for drugs which could be used to treat NSCLC patients.
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