Targeting RAS driven tumour immune evasion

ongoing

Mutations in RAS oncogenes are responsible for driving some 20% of all human malignancies, occurring in many major killers, such as lung, pancreatic, and colon cancers, but attempts to develop therapeutic interventions for RAS mutant cancers have yet to provide clinical benefit. By inhibiting pathways downstream of RAS along with other key signaling nodes, we have developed combination therapies that cause major regression of KRAS mutant lung cancer in mouse models. However, a major limitation is that the tumours are not eradicated and rapidly recur once treatment is withdrawn. Lung cancer is partly responsive to immunotherapies in the clinic, suggesting dependence on immune evasive signaling. We would like to understand whether RAS driven oncogenic signaling pathways act to protect tumours from the immune system. If so, what mechanisms does RAS use to evade tumour immune destruction and can these be specifically targeted to unleash the immune system on the tumour? Could we develop effective therapies rationally combining these with our existing RAS pathway therapies to achieve complete tumour eradication? We will use clinical samples to establish whether activation of RAS signaling pathways correlates with the ability of lung tumours to evade the immune system and by what mechanisms. We will develop appropriate preclinical models to test the impact of targeting immune evasion in RAS driven lung cancer, recognising the major limitations of existing mouse models for this purpose. We will also utilize these immunogenic preclinical models to seek novel mechanisms of tumour immune evasion, including through the use of in vivo functional genomic screens. Finally, we will establish how our existing optimal strategies for achieving RAS signaling pathway inhibition in lung cancer impact on the tumour immune microenvironment and establish strategies for combining these with interventions to subvert immune evasion, thus enabling optimal immune-assisted tumour destruction.