Our team’s reading recommendation for this month is “The current state of the art and future trends in RAS- targeted cancer therapies”, a very edifying scientific review conducted by SR Punekar et al.[i] and recently published in “nature reviews clinical oncology”.
The RAS pathway is responsible for proliferation during the life cycle of the cell. Moreover, RAS effectors are responsible for the activation of the cellular machinery not only in the dividing cells but also in differentiating cells. A dysfunction of this pathway is the origin of several cancers. Indeed, the mutation of one of these effectors could lead to an aberrant activation of a key transcription factor causing the appearance of several cancerous manifestations. Among these mutations, we find a mutation in the KRAS protein which is the inactive state of the RAS protein, one of the most important proteins of the RAS pathway. This alteration is the most frequent in solid tumors found in17% of all solid tumors.
Several research studies have been conducted to target the mutated RAS protein in its active and inactive states. This treatment consists in the use inhibitors. These showed at first promising results in patients with KRAS G12C mutant cancers. However, it was soon found that the long-term outcome of this treatment is very modest due to primary or acquired resistance to it. This resistance is manifested by an alteration of the tumor microenvironment, during treatment, leading for example to a decrease in the frequency of KRAS G12C expressing alleles or by remodeling the tumor environment which promotes immune evasion.
To circumvent this problem, given that the RAS pathway is a multilevel mediating pathway, an approach that involves a combination of targets in a vertical manner (combination of inhibitors of the same pathway) seemed to be a good approach to limit adaptive resistance and prolong responses to KRAS G12C inhibitors. While this approach has shown more efficacy, resistance was still inevitable. In this context, another horizontal approach was also explored, involving additional mediators of different pathways in a purpose to have a potential synergistic approach with KRAS inhibitors. But this also led to resistance and, even toxicity.
Indeed, mutation at the level of KRAS modifies not only the behavior of tumor cells but also the tumor microenvironment which could have an indirect impact on the immune response by creating a state of immunosuppression. These complex cellular processes promote tumor invasion and a strong resistance.
Given the complexity of the RAS pathway, curative strategies to combat this resistance require a more sophisticated understanding of this phenomena in order to decipher the origin of treatment inefficiency. This does not prevent other therapies or combinations of therapies from being investigated. In this respect, a brief example is the promising siRNA-based approaches of which anti-cancer activities have been recently discovered.
[i]Punekar SR, Velcheti V, Neel BG, Wong KK. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol. 2022 Oct;19(10):637-655. doi: 10.1038/s41571-022-00671-9. Epub 2022 Aug 26. PMID: 36028717; PMCID: PMC9412785.