Optimising the clinical use of DNA repair inhibitors
In 2005, we identified the synthetic lethal relationship between small molecule PARP inhibitors and loss of function mutations in the tumour suppressor genes BRCA1 and BRCA2, work pioneered by Alan Ashworth.
In the subsequent years since this finding, we have focused upon identifying novel genetic determinants of PARP inhibitor sensitivity and resistance as a means to refine how these drugs are used in the clinic. Part of this work has involved identifying secondary mutations in BRCA2 that drive PARP inhibitor resistance, an observation seen not only in experimental models, but also in the clinic. Recently we identified PARP1 mutations as a cause of PARP inhibitor resistance (Pettitt, Krastev et al Nature Communications 2018) as well as defects in the Shieldin complex (Noordermeer et al Nature 2018).
Our ongoing work is focused upon devising therapeutic approaches that either delay the onset of drug resistance or target the particular molecular composition of PARP inhibitor resistant tumours.
Mutations in PARP1 (coloured red) that cause PARP inhibitor resistance identified via high-density CRISPR-Cas9 mutagenesis screening. From Pettitt, Krastev et al Nature Communications 2018.
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Systematic identification of synthetic lethal interactions that operate in cancer
As cancer cell genomes are being unveiled at a breathtaking pace, we now have an enhanced understanding of the mutational events that drive cancer. Despite this understanding, for many patients, targeted therapy approaches do not exist or where they do, drug resistance limits their effectiveness.
To address these issues, one of our aims is to systematically identify synthetic lethal interactions that operate in tumour cells. Using a series of functional genomics approaches, such as the use of high-throughput genetic screens, we are currently assessing the possibility that many of the “undrugged” cancer driver gene mutations could be targeted with a synthetic lethal approach. Much of this focus is directed at understanding and exploiting synthetic lethal approaches in breast cancer, but the principles that apply in the study of this disease might also be relevant in the dissection of other cancer types. For example, we recently identified ROS1 inhibition as being synthetic lethal with E-cadherin defects in breast cancer (Bajrami et al Cancer Discovery 2018), and found that the kinase and bromodomain containing transcription factor TAF1, and multiple components of the SCFSKP Cullin F box containing complex represent synthetic lethal targets in Rb defective triple negative breast cancer (Brough et al Oncogene 2018).
The synthetic lethal effect of the ROS1 inhibitors foretinib and crizotinib in E-cadherin defective breast tumours in mice. From Bajrami et al Cancer Discovery 2018.
As well as exploiting the synthetic lethal principle to identify novel therapeutic approaches to the disease, we are also interested in understanding how genetic interactions influence the response to cancer therapy. For example, many of the well-understood cancer drug resistance mechanisms might be viewed as either functional buffering or synthetic rescue effects. Again, using a series of functional genomics approaches, much of our effort is aimed at identifying the genes that control drug sensitivity and resistance in cancer. In doing so, we hope to devise optimised therapeutic approaches for the disease that limit the impact of drug resistance.
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