The RAS protein is pathologically altered in a wide range of cancers: it causes around 40% of colorectal cancer cases and over 90% of pancreatic cancer cases, the deadliest of all cancers. A new drug targeting RAS would be a real game-changer for cancer therapy. However, RAS was long considered undruggable because it is very difficult to target using common pharmaceutical approaches. And although the first RAS drug for the treatment of lung cancer was approved in 2021, the development of further drugs remains complex and costly. New, alternative strategies could provide a solution here.
Cancer RNA on the hook
An American research team, in collaboration with MPI researchers in Dortmund, has recently developed a promising alternative approach to cancer therapy.
The concept behind it is ingenious: instead of disabling the cancer protein itself, its production is halted. This is achieved using a specially designed chimeric molecule (RIBOTAC), which binds to the pathogenic RNA at one end and has a chemical 'hook' at the other. This hook captures RNA-degrading enzymes, which break down the bound RNA and thus prevent the production of the protein.
Unexpected results
Based on this new concept, Peng Wu's team has now developed a new RIBOTAC targeting the mRNA of the cancer protein NRAS. Although the RIBOTAC was shown to degrade the mRNA, the researchers could not detect any significant difference in the total amount of the protein. They suspect that only a sub-form of NRAS, present in small quantities, was eliminated. But this is precisely where the surprise came: Despite the minimal impact on the total protein quantity, the treated cancer cells changed their appearance dramatically.
Fundamental dogma of drug research called into question
"The molecules left a biological fingerprint that does not match any known class of active substances," explains Peng Wu. "This suggests that we are targeting entirely new signalling pathways or mechanisms." With their findings, the researchers are challenging a fundamental dogma of drug research: Until now, it was assumed that a therapeutic effect could only be achieved if a significant proportion of the target RNA or protein was impacted (e.g. inhibition, activation, or degradation). In this study, however, the removal of even a tiny fraction of RNA (<1%) resulted in extensive cellular changes.
In future, the team plans to decipher the mechanisms influenced by the RIBOTAC and wants to investigate how this influence affects cancer cells. At the same time, the chemistry and binding strategy are to be further optimised to produce improved next-generation "molecular erasers".
