The approaches we currently take in Manchester and UCL are, on the one hand, to identify genetic drivers of lung cancer and lung cancer therapy resistance, with a particular focus on mutations in components of survival pathways, and, on the other, to devise targeted therapeutic combinations that specifically induce programmed cell death by apoptosis in lung cancer cells.
Regarding the first approach, we use (i) bioinformatics tools and structural modelling to evaluate the functional impact of somatic mutations in novel or understudied kinases identified in cancer genomic screens or drug resistance screens, (ii) genetic dependency screens to identify important genetically altered drivers of cancer or mediators of therapeutic resistance, and (iii) mining of cancer genomic data portals to identify frequently amplified kinases that harbour pathological somatic mutations. The overall goal of this approach is to identify common and convergent pathways utilised by cancer cells to promote tumour growth and adaptation, which can be therapeutically targeted.
The aims of the second approach are (i) to determine the therapeutic efficacy of novel pro-apoptotic targeted therapeutic combinations in the most advanced in vivo models of lung cancer and (ii) to identify the mechanisms of resistance – and how we may be able to target them therapeutically – that characterise cancers that emerge as resistant to even the most highly effective of these therapies by multilevel data analysis which includes genomic, proteomic and tumour microenvironmental profiling.
Our ultimate aim is to determine how best to combine the inhibition of genetic drivers of lung cancer with targeted apoptosis inducing therapies in individual lung cancer patients. As such, we will investigate the interplay between the molecular alterations induced by targeting survival pathways that are upregulated in individual cancers with specific kinase inhibitory therapies and the triggering of the apoptosis machinery by targeted combination therapies. Finally, we will examine this interplay on the biochemical, genomic and proteomic level using human lung cell lines, primary human lung cancer cells and the most advanced murine in vivo models of lung cancer.
The Centre will draw on Manchester’s strengths in elucidating genetic drivers of lung cancer, with its special focus on kinases in survival pathways, and UCL’s strength in devising novel apoptosis based therapies for lung cancer, in order to develop a number of novel targeted therapies.