Facts and hopes on RAS inhibitors and cancer immunotherapy.

While the past decade has seen great strides in the development of immunotherapies that reactivate the immune system against tumors, there have also been major advances in the discovery of drugs blocking oncogenic drivers of cancer growth. However, there has been very little progress in combining immunotherapies with drugs that target oncogenic driver pathways. Some of the most important oncogenes in human cancer encode RAS family proteins; although these have proven challenging to target, recently drugs have been approved that inhibit a specific mutant form of KRAS, G12C. These have improved the treatment of lung cancer patients harboring this mutation but development of acquired drug resistance after initial responses has limited the impact on overall survival. Due to the immunosuppressive nature of the signaling network controlled by oncogenic KRAS, targeted KRAS G12C inhibition can indirectly affect anti-tumor immunity, and does so without compromising the critical role of normal RAS proteins in immune cells. This serves as a rationale for combination with immune checkpoint blockade, which can provide additional combinatorial therapeutic benefit in some pre-clinical cancer models. However, in clinical trials, combination of KRAS G12C inhibitors with PD-(L)1 blockade has yet to show improved outcome, in part due to treatment toxicities. A greater understanding of how oncogenic KRAS drives immune evasion and how mutant specific KRAS inhibition impacts the tumor microenvironment can lead to novel approaches to combining RAS inhibition with immunotherapies.