Final Report Summary - RASTARGET (Targeting RAS oncogene addiction)
While the early signalling events activated by RAS are well characterised, targeting RAS effector pathways in isolation have failed clinically, with MEK inhibition proving entirely ineffective in KRAS mutant lung cancer in a phase 3 trial. One focus of our work has been to investigate combinatorial approaches to therapeutic targeting of RAS mutant cancers by inhibiting downstream pathways along with other key signaling nodes through the use of large scale functional genomic screens. This has led to the identification of therapeutic combinations that can cause major sustained regression of KRAS/p53 mutant lung cancer in mouse models. We have also applied these combinatorial approaches to optimize the use of direct inhibitors of G12C KRAS, which represent a significant advance in attempts to target RAS directly. Specifically, combination treatments with KRAS or MEK inhibitors joined with IGF1R and mTOR inhibitors show particularly strong activity towards RAS mutant cancers.
A major limitation of these approaches is that the tumours rapidly recur once treatment is withdrawn: eradication of these tumours has so far proved impossible. This, however, is not a problem limited to therapy of RAS mutant cancers: in the case of EGFR mutant lung cancer or BRAF mutant melanoma, where efficient inhibitors of the driver oncoproteins have been developed, therapy causes impressive short-term responses but fails to cure due to rapid evolution of drug resistance. Bearing these challenges in mind, we have sought to identify other vulnerabilities of RAS mutant cancers that might open the way to tumour eradication when combined with optimal proliferative signaling pathway inhibition.
As lung cancer has proven to be at least somewhat responsive to immunotherapies, suggesting that these tumours are dependent on ongoing immune evasive signaling, we have sought to understand the largely unresolved question as to whether the common oncogenic driver pathways, and in particular RAS driven signaling pathways, specifically act to protect tumours from the attention of the immune system, or whether this immune evasion by tumours is mediated by selective pressure acting orthogonally to the proliferative control signaling mechanisms. For some oncogenic driver pathways, such as β-catenin, clear evidence has emerged for its control of a specific immune evasive mechanism. We have now shown in the case of RAS mutant cancers that RAS signaling promotes a transcriptional programme that includes many immunoregulatory factors, including many inflammatory cytokines and chemokines, and specifically controls expression of the immune checkpoint protein PD-L1 through modulation of the stability of its mRNA. but their overall impact on tumour interaction with the host immune system is less well defined. This has allowed us to establish strategies for combining RAS signaling pathway inhibition with interventions to subvert immune evasion to enable optimal therapeutic response against lung cancers with RAS pathway activation, with the ultimate aim of immune-assisted tumour eradication.