Beyond the breakthrough: developing new ways to target hard-to-treat cancers

KEY TAKEAWAYS:

• Kevan Shokat’s breakthrough in targeting the once “undruggable” K-Ras protein has opened a new therapeutic path, offering hope for treating cancers with notoriously poor survival rates.
• His lab is building on this progress by uncovering how Ras-driven tumors develop drug resistance and considering strategies to counteract it.
• They are also exploring whether mutation-targeted drugs could be used proactively to prevent cancers from developing or advancing.

Curiosity-driven scientific research is the ultimate long game: the end goal is clear, but the different paths to achieving it only reveal themselves in time.

HHMI Investigator Kevan Shokat devoted his career to so-called “undruggable” proteins, hoping that his work would ultimately contribute to potential treatments or cures for cancer. Twelve years after unlocking the famously tricky mutant K-Ras protein, Shokat’s work now underlies a promising new treatment for pancreatic cancer— an illness with a five-year survival rate of only 13 percent. 

Until 2013, the K-Ras mutation posed a major obstacle to developing effective cancer treatments. It is the single most commonly mutated oncogene in human cancers, appearing in 90 percent of pancreatic cancers, 40 percent of colon cancers, and 20 percent of non-small cell lung cancers.

The Ras family of genes controls how cells grow and divide. When K-Ras genes mutate, they get stuck in the “on” position, propelling cells’ constant growth.

Previous attempts to design drugs that target Ras proteins were stymied by the molecule’s smooth, compact shape, which provided no obvious drug-binding “pockets.” Shokat identified a less-studied cysteine mutation and exploited its chemical properties to successfully tether drugs to the K-Ras mutation.

That breakthrough has since opened the way for researchers to tackle other K-Ras mutations. Now Shokat and his lab at the University of California, San Francisco, are using chemical genetics to explore different strategies to capitalize on their original breakthrough, coupled with the new information they are learning from patients.

Overcoming Resistance to Ras-Targeted Cancer Drugs

Shokat’s discovery led to the development of sotorasib and adagrasib, Ras-targeting drugs approved to treat lung and colon cancers, as well as daraxonrasib, which is currently in clinical trials. Although many patients initially benefit from each of these treatments, most eventually develop drug resistance.

This raises a new research question for Shokat and his team — how best to overcome that resistance. Many cancer-driving proteins evolve new mutations when exposed to drugs, but the recent clinical trials for K-Ras inhibitors show that these tumors adapt differently: they amplify their own genomic locus, producing up to 70 additional copies of the Ras protein. This pattern suggests that the tumor is uniquely dependent on Ras and cannot easily switch to alternative growth pathways.

Shokat believes that drug resistance could be curbed by introducing the right Ras pathway inhibitor as soon as the patient begins targeted cancer therapy, thereby clamping down tumor growth before it can amplify itself.

Now that they’ve seen exactly how the protein develops resistance, they can model it in labs, rather than waiting for additional clinical data. Already, the next generation of more than 50 Ras inhibiting drugs in the development pipeline show promising results of decreased drug resistance.

Turning Reactive Treatment into Proactive Prevention

As drug development advances and treatments become increasingly tailored to specific mutations, researchers are beginning to ask whether they might also be used preventatively.

Although these precision oncology therapies were designed for late-stage cancers, the relevant mutations can be detected in patients early in the disease or even before it develops. In theory, then, such drugs could suppress the mutation before it can develop into a tumor. This idea is still in its early stages, but it represents an especially promising direction given the critical importance of cancer prevention in public health.

Rescuing Tumor Suppressor Function

When K-Ras mutations drive cancer, they often impair key tumor suppressors like p53 – a protein essential for maintaining cell health. Tumor suppressors use multiple pathways to attack tumors, so they are a particularly powerful tool in fighting cancer. Shokat is investigating the possibility of restoring function to these protective proteins, effectively reawakening them. However, this approach poses a distinct challenge: while most drugs are designed to shut down some cellular function, this approach requires reactivating one.

Several years ago, Shokat’s lab developed a molecule that corrects the misfolding of a mutant form of p53, thereby rescuing its tumor suppressor function. If a drug could simultaneously inhibit the K-Ras oncogene — as the current cancer drugs do — and also leverage the power of tumor suppressors like p53, Shokat believes that it could shatter the cell’s ability to grow in its altered, cancerous state.

As he pursues these different possible pathways to cancer treatments, Shokat never loses sight of the initial discovery that made them possible. “If we’d followed the conventional wisdom of biochemistry and genetics, we would never have overcome these undruggable proteins,” he says. “When we question our assumptions, that’s when opportunities for discovery open up.”