Fighting Cancer with New Therapies Targeting Deadly Mutations
Cutting-edge chemistry and innovative drug development strategies are bringing us closer to overcoming a deadly cancer-causing protein mutation that was once thought to be untreatable.
A protein known as KRAS is often mutated in some of the most fatal types of cancers. Developing medications to neutralize KRAS has been a difficult task. However, there is newfound optimism this year. A clinical trial for a drug that aims to breakdown a form of mutated KRAS has shown promising results. Furthermore, there are four large-scale clinical trials underway to test another medication that aims to block several different mutated forms of KRAS and related proteins. The results of the first trial are anticipated in the coming months.
Combination Strategies to Overcome Resistance
While these strategies show promise, it is unlikely that they will be a standalone cure, as stated by Dieter Saur, a well-known gastroenterologist and cancer researcher. The expectation is that these new drugs can be combined with each other or with other treatments to create a therapy strategy that KRAS-mutant cancers cannot resist.
"It's an exciting time. So many different things are happening," Saur remarks. "The field has undergone a complete transformation."
Targeting the On/Off Switch of a Protein
As a member of the RAS family of proteins, KRAS plays a vital role in cell growth and proliferation. Certain KRAS mutations can keep the protein in an 'on' state, causing uncontrolled cell growth, a key characteristic of cancer.
This feature made KRAS an attractive target for cancer drug development. The idea was to find a drug that could turn it off, thereby stopping the tumor growth. However, the protein’s relatively smooth surface made it difficult for drug developers to design molecules that could bind to and inhibit the protein.
When compounds were finally discovered that could bind to and neutralize mutant KRAS, these drugs were effective for only a short period. "In every patient, we see resistance developing," Saur explains. "It's not a cure."
Resistance to these medications can take several forms, including new mutations in the KRAS protein, and other cellular processes being activated to make up for the loss of KRAS function. One hope was that some of this resistance could be circumvented if a drug could completely eliminate the mutated KRAS protein.
Marking the Protein for Destruction
Enter the new class of drugs called degraders. These compounds bind to KRAS and then link it to another protein, known as an E3 ubiquitin ligase. This ligase chemically marks KRAS for cellular disposal, leading the cell’s waste-processing machinery to breakdown the protein and get rid of it.
This process is intricate and difficult to manipulate, according to Kevan Shokat, a chemical biologist. "The amount of complexity and gymnastics that has to happen — sometimes your protein can get degraded, sometimes it just can't," he says.
Despite the challenges, oncologists like Wungki Park are drawn to the potential of KRAS degraders. "You can actually re-educate the cell: 'hey, this is disposable, just remove it'," he says.