For decades, KRAS, one of the most deadly cancer-causing mutant proteins, was considered impossible to target due to its smooth surface and lack of binding pockets.
Dealing with the growth of cancer cells has always been challenging, causing constant frustration in the scientific community.
KRAS also poses a “nonsense” challenge, acting like an “on/off” switch for cell growth. Mutations switch it off in the “on” state, leading to uncontrolled tumor growth.
Furthermore, its smooth physical structure makes it difficult for conventional drug molecules to “stick to” it and inactivate it.
Now, new hope has been rekindled as the drug makes a game-changing breakthrough during trials. New strategies, particularly protein degraders and multi-mutant inhibitors, are showing success in clinical trials.
Recent Successes
In a clinical trial, a drug has shown efficacy against mutant KRAS proteins. Another four trials are also ongoing, demonstrating effective inhibition against several different mutant forms of KRAS and related proteins.
The drugs act as protein degraders. Instead of simply blocking the protein, these drugs bind KRAS to an enzyme called E3 ubiquitin ligase.
The enzyme marks KRAS as “cellular garbage”, prompting cells to physically destroy the mutant.
“As much complexity and gymnastics as it takes, sometimes your protein may degrade, sometimes it may not,” said Kevan Shawkat, a chemical biologist at the University of California, San Francisco.
In March, researchers reported promising results for the first KRAS degrader to be tested in humans. In a recent trial a drug called cetidegrasib, made by Astellas Pharma in Tokyo, caused tumors to shrink in more than 1/3 of lung cancer patients and 1/4 of pancreatic cancer patients.
In another breakthrough development, an inhibitor called daraxonrasib inhibited active but different forms of KRAS and its related mutants, disrupting their ability to promote cancer.
Major Challenges
One of the biggest challenges is the drug resistance displayed by cancer cells due to its greater adaptability.
Resistance comes in different forms, including new mutations developed by KRAS or the cell may activate backup pathways to drive tumor growth even if KRAS is disabled.
Combination therapy: the next frontier
According to experts including Kevan Shawkat and Dieter Sauer, the next breakthrough lies in “combination therapy.” Even data suggests that different types of inhibitors may prove more effective than a single use.
“If we combine them in the right way, we can get huge synergy. It’s just a matter of time,” Shaukat said.
