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Suppression of Enzymes Required for Progression of LUng Cancer

Final Report Summary - SERPLUC (Suppression of Enzymes Required for Progression of LUng Cancer)

State-of-the-Art: Cancers of the Lung currently account for roughly 1 in 5 deaths from Cancer across the EU and the 5-year survival rate from time of diagnosis is just 10%. Personalised therapies, available for lung cancers with mutations in EGFR and ALK1, have improved patient outcomes in recent years. However, such tumours represent a minority and the emergence of resistance to personalised therapies remains an on-going problem. Perhaps the greatest challenge facing the field of lung cancer is that patients typically present quite late with advanced heterogeneous disease that is extremely difficult to treat effectively. Genetically engineered mouse models of cancer have the potential to dramatically enhance our understanding of lung cancer because they enable the study of the entire course of disease development of time from the first day of tumour initiation. SERPLUC aims to use such a mouse model to understand the mechanisms of progression of early stage lung cancer with the long-term goals of 1) identifying novel targets for specific treatment of lung cancer and 2) identifying the molecular signatures of early stage cancer that may in future lead to assays for early detection and screening of patients at high risk of lung cancer development.
Progress to date: In Phase 1 of the project, we identified over 450 genes, of which, over 150 can be classified as Enzymes, whose expression increases significantly during progression of lung cancers to invasive disease. We have verified that many of these genes remain important for viability of human lung cancer cells and identified a subset that participate in facilitating cell migration, which is a key hallmark of invasive disease. In Phase 2 of the project we validated the functional contribution of a specific subset of these enzymes, targeting particularly receptor tyrosine kinases (RTK)s and other kinases involved in RAS pathway signalling. In particular, amongst the significantly upregulated genes associated with tumour progression, we identified several non-enzymatic ligands of EGFR/ERBB family RTKs. This observation was striking for 2 reasons – firstly, that ERNBB RTKs have heretofore not been thought to participate in cancers driven by RAS mutation and secondly, while there are no clinically proven RAS inhibitor available, several ERBB RTK inhibitors are approved for use in cancer patients. We have found that treatment of KRAS driven lung cancers with multi-ERBB inhibitors leads to a significant extension of lifespan in mice – strongly suggesting that human cancer patients, for whom no targeted therapies are presently available, could rapidly benefit from use of these drugs.