Much of the work in the group has focused on the RAS family of oncogenes and the signalling pathways that they control. RAS genes are activated by point mutation in some 20 per cent of all human tumours and are known to play a key role in the establishment of the transformed phenotype.
While the signalling pathways activated by RAS are well characterised, it remains a major challenge to identify what proteins are selectively important in the establishment and maintenance of the RAS transformed phenotype and may therefore act as potential therapeutic targets for cancer treatment.
We have employed functional genomics approaches using gene silencing by genome-scale libraries of RNA interference agents to investigate this, along with the use of genetically engineered mouse models of human cancer.
When cells become progressively transformed during the evolution of cancer, they suffer stresses that are not seen by normal cells and become increasingly dependent on stress management pathways. This means that the tumour cells show a unique set of dependencies, both on the oncogenic drivers and also on stress handling pathways, sometimes termed oncogene addiction and non-oncogene addiction, respectively.
We have investigated these dependencies by RNAi screening, comparing a cancer cell line containing an activated KRAS allele with a normal ('isogenic') derivative in which this has been removed (Wang et al., 2010; Oncogene. 29(33): 4658-70), and also using a panel of 30 or so cancer cell lines, half of which were mutant and half wild type for KRAS (Steckel et al., 2012; Cell Research. 22: 1227).
This approach uncovered proteins whose therapeutic targeting might be expected to provide differential toxicity towards KRAS mutant tumour cells. One example of a determinant of non-oncogene addiction found in this way, the transcription factor GATA2, has been investigated in detail. Using genetic mouse models, we could show that the development and continued maintenance of KRAS induced lung cancer is uniquely dependent on the expression of GATA2: when this is blocked, the lung adenocarcinomas regress completely. As a transcription factor, GATA2 itself is not likely to be a good drug target. However, using a range of methods to investigate the transcriptional programme controlled by GATA2, we identified a number of downstream pathways that can be inhibited by existing drugs.
Using a combination of two such drugs we have been able to show an impressive therapeutic response in KRAS induced mouse lung cancer models (Kumar et al., 2012; Cell. 149(3): 642-55). We are now investigating the possibility of studying this drug combination in a clinical setting.
In addition, we have also been interested in investigating mechanisms of development of resistance of tumours to initially effective therapies and have used the example of resistance to EGFR tyrosine kinase inhibitors (TKI) in EGFR mutant lung cancer. Using a genome-wide siRNA screen, we found that erlotinib resistance was associated with reduced expression of neurofibromin, the RAS GTPase-activating protein encoded by the NF1 gene. A subgroup of patients with EGFR-mutant lung adenocarcinoma and low NF1 expression could benefit from combination therapy with EGFR and MEK inhibitors (de Bruin et al., Cancer Discovery 2014).