Gene Function Group

Although tumour cells gain a series of characteristics that provide a selective advantage, the mutational events that drive these processes also impart upon the cell a series of dependencies. One focus of our work has been in identifying and understanding these tumour specific dependencies, such as synthetic lethal effects. As well as identifying these effects, the central aim of our laboratory is to use this information to either: (i) inform the design or interpretation of clinical trials in cancer; (ii) to understand why and how some patients respond to treatment, whilst others do not; and (iii) to identify novel drug targets and therapeutic approaches to treating cancer.

We have made major advances in identifying novel synthetic lethal interactions that have translational potential, the most notable being the identification of synthetic lethality between PARP inhibitors and genes involved in the homologous recombination pathway such as BRCA1 and BRCA2. Using this same concept, we have also made advances in systematically identifying additional synthetic lethal effects that operate in breast cancer and other cancers with tumour suppressor defects in genes such as ARID1A (Williamsonet al Nature Communications 2016), E-cadherin (Bajrami et al Cancer Discovery 2018) andRb (Brough et al Oncogene 2018).We also have a significant interest in understanding the genetics of drug resistance in cancer, using pre-clinical approaches to either identify or understand mechanisms of drug resistance that operate clinically. At present, we are using systematic in vitro and in vivo screens (e.g. Pettitt, Krastev et al Nature Communications 2018, and Noordermeer et al Nature 2018) to understand the genetic basis of drug sensitivity and resistance to a wide variety of drugs. Again, our aim in carrying out this work is to generate information that could be used to inform the clinical management of the disease, either in the form of uncovering novel biology, identifying predictive biomarkers of drug response or in designing therapeutic approaches that could either minimise the frequency of drug resistance or at least delay its emergence.Underpinning these research objectives has been a continuing focus on exploiting both commonly used as well as high-throughput (HT) functional genomic approaches. The laboratory houses a series of HT platforms, including HT siRNA, shRNA, drug, CRIPSR-Cas and transposon mutagenesis systems, and we will continue to augment these with novel technologies as appropriate. We apply a multidisciplinary approach to our work, and host within the group cell biologists, geneticists, biochemists, in vivo specialists, bioinformaticians and clinicians, all of whom work towards the same aims.