targets entering our discovery portfolio identified through this approach. Furthermore, there is an urgent need to explore

novel therapeutic spaces. Drug development research is focused on targets that are believed to be ‘druggable’, such as kinases or cell surface receptors that can be targeted with small molecule inhibitors. By targeting every single gene in the genome and understanding the networks in which they function, hand in hand with new modality approaches such as antisense oligonucleotides8, we can expand the therapeutic world that is available to us. One area of particular interest is the DNA dam-

age response. Alterations in genes involved in var- ious DNA damage response and repair mecha- nisms can have a profound impact on the risk of cancer, tumour progression and response to vari- ous types of therapy. For example, women carrying a germline mutation in BRCA1 or BRCA2 have a significantly increased risk of developing breast or ovarian cancer due to errors in the homologous recombination DNA pathway. However, inhibiting an alternative repair pathway mediated by PARP results in chromosomal instability and cell death, as the cancer cells are left without any kind of functional DNA repair9. The discovery of this ‘one-two punch’, known as

synthetic lethality, led to the approval of the first- in-class PARP inhibitor, olaparib. We are now using a functional genomics approach to map out the landscape of synthetic lethality in cancer cells, searching for similar combinations of co-depen- dent pathways that can be manipulated using drugs or other therapies. Another key area of interest is identifying and

targeting mechanisms of resistance to cancer ther- apy in metastatic disease. It is becoming increasing- ly clear that the underlying genetic heterogeneity within a tumour will inevitably generate clones of resistant cells that emerge as a result of the selec- tive pressure applied by treatment, meaning that a patient whose disease initially responds to therapy will ultimately relapse. Using our functional genomics platform, we can investigate the impact of manipulating thousands of genes in cancer cells that have become resistant to a particular therapy to uncover the molecular mechanisms of resis- tance. While it might seem like there are infinite ways

that cancer cells can evade the effects of treatment, it is more likely that there is a limited number of escape routes depending on the cancer type and the therapies employed. Some types of cancers will pre- fer to ‘rewire’ in certain ways – which may depend

Drug Discovery World Spring 2019

on their developmental history and tissue of origin – but this is potentially predictable and can be uncovered using a functional genomics approach. For example, the presence of a T790M mutation

in the epidermal growth factor receptor (EGFR) gene is the most frequent mechanism of acquired resistance in non-small cell lung cancer patients, appearing in around 60% of tumours that initially responded to first-generation EGFR inhibition10. Identifying the landscape of genetic alterations

that might make a cancer resistant to a given drug could reveal potential targets for novel therapies that overcome or prevent resistance. We can also use AI to tease out potential combinations of ther- apies that would create a ‘double bind’ of mutually exclusive resistance mechanisms in tumour sub- clones11. As well as understanding the general mechanisms

of drug resistance in various cancer types, we can also use our functional genomics platform to inves- tigate the phenomenon of drug tolerant persister cells12 that neither proliferate nor die, creating a ‘sleeper pool’ from which highly-resistant clones can eventually emerge. CRISPR screening could reveal key genes responsible for dormancy and reactivation, identifying targets for more effective therapies that prevent long-term relapse and signif- icantly extend survival from metastatic disease. In addition to using CRISPR to leverage the

genome to improve drug discovery, there are fur- ther opportunities for AstraZeneca to better under- stand and improve the tools themselves; for exam- ple, by increasing the accuracy of targeting and reducing off-target effects or by improving the delivery of CRISPR tools into cells.

A collaborative effort The Functional Genomics Centre is based at the new Milner Therapeutics Institute13 in Cambridge, right next door to our global headquarters and strategic R&D centre within the biggest life sci- ences research hub in Europe. The Milner Therapeutics Institute provides a unique collabora- tive space and environment on the Cambridge Biomedical Campus. The initiative consolidates expertise across the

academic, clinical, charitable and industrial sectors to create standardised, bench-marked platforms for discovery science. It is being established under the guidance of world-leaders in functional genomics, including Professor Greg Hannon, Director of the Cancer Research UK Cambridge Institute. Our investment is pushing the UK to the forefront of CRISPR applications and bringing vital new insights into cancer, leveraging the secrets


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