Title: Oncogenic Ras signalling in transformation
Funder: The Francis Crick Institute

Abstract: The focus of my laboratory at the Francis Crick Institute is on characterisation of the molecular mechanisms involved in tumorigenesis by RAS oncogenes with a view to identifying novel therapeutic strategies for RAS mutant cancers. The RAS family of closely related oncogenes (KRAS, NRAS, HRAS) constitute the most frequently mutated drivers in human cancer, being activated in some 20% of tumours, including many poor prognosis cancers such as those of the lung and the pancreas. Despite huge research efforts, at present it is not clinically possible to target the RAS protein directly, although drugs have been developed that target downstream signaling pathways controlled by it, such as the RAF/MEK pathway and the PI 3-kinase/AKT pathway. MEK inhibitory drugs have shown only very modest benefit in KRAS mutant lung cancer, and have failed to demonstrate efficacy in phase III clinical trials. To try to find new approaches to the therapeutic targeting of RAS mutant cancers, my laboratory has investigated dependencies of RAS mutant lung cancer cells using combinatorial drug library screens targeting downstream effector pathways of RAS, along with genome wide RNAi drug sensitization screens. This has revealed synergistic dependencies of RAS mutant cells on both MEK and insulin-like growth factor receptor (IGF1-R) signaling input, with further efficacy provided by inhibition of mTOR. These combinations provide good control of aggressive KRAS mutant lung cancer, but fail to eradicate the disease. To find novel therapeutic targets, we have also carried out a series of large-scale functional genomic screens to probe for unique dependencies of RAS mutant cancer cells. These “synthetic lethal” screens have highlighted a number of vulnerabilities of RAS mutant cells, including dependence on the function of the transcription factor GATA2, the origin of DNA replication complex protein CDC6 and, in the case of cells that have undergone epithelial mesenchymal transition, the transcriptional regulator SNAIL2. However, these acquired dependencies of RAS mutant cancer cells have proven to be context dependent and not sufficiently robust to yield a lasting therapeutic benefit in models of advanced cancers. In order to move beyond treatments that only delay advanced cancers for a few months or, at best, years, we need to understand how to eradicate tumour cells completely, not leaving minor populations that go on to develop drug resistance and cause disease relapse. Tumours have to find ways to avoid recognition as foreign by the immune system, and recent clinical trials have achieved remarkable response rates using immune checkpoint inhibitors as immunotherapies in certain advanced cancers. We are investigating how RAS pathway signaling alters the interaction of RAS mutant tumours with the immune system. We have characterized specific mechanisms whereby RAS signaling controls the expression of immune checkpoint proteins through regulation of the stability of their mRNAs. We have also been developing improved genetically engineered mouse models of RAS oncogene driven cancers that contain rates of mutation and aneuploidy elevated to the levels seen in human cancers in the clinic and are using these immunogenic genetically engineered mouse models (iGEMMs) to study the interaction of the tumour with the immune system from the earliest stages of tumour development, which is not normally possible in tumour transplantation models.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS