Exploiting genetic concepts and approaches to understand cancer biology and therapy
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 team cell biologists, geneticists, biochemists, in vivo specialists, bioinformaticians and clinicians, all of whom work towards the same aims.
Bajrami I, Marlow R, van de Ven M, Brough R, Pemberton HN, Frankum J, Song F, Rafiq R, Konde A, Krastev DB, Menon M, Campbell J, Gulati A, Kumar R, Pettitt SJ, Gurden MD, Cardenosa ML, Chong I, Gazinska P, Wallberg F, Sawyer EJ, Martin LA, Dowsett M, Linardopoulos S, Natrajan R, Ryan CJ, Derksen PWB, Jonkers J, Tutt ANJ, Ashworth A, Lord CJ. E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer. Cancer Discov.8(4):498-515. (2018)
Noordermeer SM, Adam S, Setiaputra D, Barazas M, Pettitt SJ, Ling AK, Olivieri M, Álvarez-Quilón A, Moatti N, Zimmermann M, Annunziato S, Krastev DB, Song F, Brandsma I, Frankum J, Brough R, Sherker A, Landry S, Szilard RK, Munro MM, McEwan A, Goullet de Rugy T, Lin ZY, Hart T, Moffat J, Gingras AC, Martin A, van Attikum H, Jonkers J, Lord CJ, Rottenberg S, Durocher D. The shieldin complex mediates 53BP1-dependent DNA repair. Nature.2018 Jul 18. doi: 10.1038/s41586-018-0340-7.
Krastev DB, Pettitt SJ, Campbell J, Song F, Tanos BE, Stoynov SS, Ashworth A, Lord CJ. Coupling bimolecular PARylation biosensors with genetic screens to identify PARylation targets. Nat Commun.9(1):2016. (2018)
Pettitt SJ, Krastev DB, Brandsma I, Dréan A, Song F, Aleksandrov R, Harrell MI, Menon M, Brough R, Campbell J, Frankum J, Ranes M, Pemberton HN, Rafiq R, Fenwick K, Swain A, Guettler S, Lee JM, Swisher EM, Stoynov S, Yusa K, Ashworth A, Lord CJ. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun. 10;9(1):1849. (2018)
Brough R, Gulati A, Haider S, Kumar R, Campbell J, Knudsen E, Pettitt SJ, Ryan CJ, Lord CJ.Identification of highly penetrant Rb-related synthetic lethal interactions in triple negative breast cancer. Oncogene.2018 Jun 18. doi: 10.1038/s41388-018-0368-z.
Lord, C.J.& Ashworth, A. PARP inhibitors: Synthetic lethality in the clinic. Science. 355, 1152-1158 (2017).
Williamson, C. T., Miller, R. E., Pemberton, H., Jones, S., Campbell, J., Kigozi, A., Badham , N., Rafiq, R., Brough, R., A., G., C., R., J., F., Vermulen, B., Reynolds, A. R., Reaper, P. M., Pollard, J. R., Ashworth, A. & Lord, C.J.ATR inhibitors as a Synthetic Lethal Therapy for Tumors Deficient in ARID1A. Nature Communications 7, 13837, (2016).
Farmer, H., McCabe, N., Lord, C.J., Tutt, A. N., Johnson, D. A., Richardson, T. B., Santarosa, M., Dillon, K. J., Hickson, I., Knights, C., Martin, N. M., Jackson, S. P., Smith, G. C. & Ashworth, A. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 434, 917-921, (2005).
Lord, C.J.& Ashworth, A. The DNA damage response and cancer therapy. Nature 481, 287-294, (2012).
McCabe, N., Turner, N. C., Lord, C.J., Kluzek, K., Bialkowska, A., Swift, S., Giavara, S., O'Connor, M. J., Tutt, A. N., Zdzienicka, M. Z., Smith, G. C. & Ashworth, A. Deficiency in the repair of DNA damage by homologous recombination and sensitivity to poly(ADP-ribose) polymerase inhibition. Cancer Res 66, 8109-8115, (2006).
Edwards, S. L., Brough, R., Lord, C.J., Natrajan, R., Vatcheva, R., Levine, D. A., Boyd, J., Reis-Filho, J. S. & Ashworth, A. Resistance to therapy caused by intragenic deletion in BRCA2. Nature 451, 1111-1115, (2008).