Recent Successes<\/span><\/h2>\nIn 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. <\/p>\n
The drugs act as protein degraders. Instead of simply blocking the protein, these drugs bind KRAS to an enzyme called E3 ubiquitin ligase. <\/p>\n
The enzyme marks KRAS as “cellular garbage”, prompting cells to physically destroy the mutant. <\/p>\n
“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. <\/p>\n
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. <\/p>\n
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. <\/p>\n
Major Challenges<\/span><\/h2>\nOne of the biggest challenges is the drug resistance displayed by cancer cells due to its greater adaptability. <\/p>\n
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. <\/p>\n
Combination therapy: the next frontier <\/span><\/h2>\nAccording 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. <\/p>\n
“If we combine them in the right way, we can get huge synergy. It’s just a matter of time,” Shaukat said. <\/p>\n<\/p><\/div>\n