New Hope for Hard-to-Treat Cancers: Targeting KRAS with Inhibition and Degradation

Scientists are developing new therapeutic strategies to target the KRAS protein, a mutant form of which is implicated in several aggressive cancers. Historically considered difficult to treat, the protein is now the subject of multiple clinical trials and preclinical studies exploring both degradation and inhibition approaches.

Summary of Key Developments

A large clinical trial has found that the experimental drug daraxonrasib nearly doubled survival in patients with a form of advanced pancreatic cancer.

In preclinical research, a separate study demonstrated that inducing degradation of the mutant KRAS protein led to greater lung cancer regression in mice than conventional inhibition.

Clinical Progress: Daraxonrasib and Other Inhibitors

Results from a clinical trial for the experimental drug daraxonrasib were presented at the American Society of Clinical Oncology annual meeting on May 31 and published in the New England Journal of Medicine. The drug, developed by Revolution Medicines, targets all three members of the RAS family of proteins.

Key Findings

• Patient Survival: Patients receiving daraxonrasib lived a median of 13.2 months, compared to 6.7 months for those receiving chemotherapy.
• Disease Context: The trial involved patients with a form of advanced pancreatic cancer.

Four large clinical trials are also evaluating another drug that inhibits multiple mutant forms of KRAS and related proteins. Initial results from one of these studies are anticipated in the coming months.

Preclinical Research: Degradation of Mutant KRAS

A study led by IRB Barcelona and the Centro de Investigación del Cáncer (CSIC, USAL, FICUS) explored a degradation strategy using PROTACs (proteolysis-targeting chimeras). The research was published in Cancer Research.

Key Findings

• Approach: Researchers used PROTACs to force degradation of the KRASG12V mutant protein in lung cancer cells.
• Results: Degradation of KRASG12V led to pronounced tumor regression in preclinical mouse models. Cancer cells stopped proliferating and underwent apoptosis.
• Mechanism: The response was observed even in immunodeficient mice, indicating the effect was primarily intrinsic to cancer cells.
• Resistance: Tumors developed resistance by altering the cellular machinery responsible for protein elimination, a distinct mechanism not previously described for traditional inhibitors.

Understanding KRAS and Treatment Challenges

KRAS is part of the RAS family of proteins, which are critical for cell growth and proliferation. Certain mutations can cause the KRAS protein to remain in an 'on' state, leading to uncontrolled cellular growth.

Historical Difficulties

• Developing drugs to target mutant KRAS was a long-standing goal that faced significant challenges.
• The protein's relatively smooth surface provided few binding pockets for drug molecules.
• Early compounds that could bind and inhibit mutant KRAS were often effective for only short periods, with patients developing resistance.
• Resistance mechanisms included new KRAS mutations and the activation of alternative cellular processes.

Innovative Degradation Approach

To address drug resistance, researchers are exploring the use of 'degraders.'

Mechanism of Action

• Degraders are compounds designed to bind to KRAS and then tether it to an E3 ubiquitin ligase.
• The ligase marks KRAS for degradation, instructing the cell's waste-processing machinery to break down and remove the protein.
• This method aims to eliminate the mutant protein entirely rather than merely inhibiting its function.

Dr. Cristina Mayor-Ruiz (IRB Barcelona, co-lead author) stated:

"KRAS inhibitors have brought about a massive shift in treatment, but resistance remains a major hurdle. Sequentially or concurrently combining inhibition and degradation could make a significant difference."

Future Outlook and Potential for Combination

Researchers suggest that these individual approaches are unlikely to provide standalone cures. The expectation is that they can be combined with each other or with existing cancer treatments to create comprehensive regimens.

Dieter Saur, a gastroenterologist and cancer researcher at the Technical University of Munich, stated that these individual approaches are unlikely to provide a standalone cure, and the expectation is that they can be combined with each other or with other drugs to develop treatment regimens that KRAS-mutant cancers cannot evade.

Experts hope success in targeting KRAS may lead to treatments for other challenging cancer targets, such as the MYC and p53 proteins.

Contributors and Funding

The preclinical degradation study involved researchers from IRB Barcelona, the Centro de Investigación del Cáncer, the University of Salamanca, the University of Navarra, the Catalan Institute of Oncology, the University of Liège, the University of Turin, CIBERONC, and the University of Barcelona.

Funding was provided by:

• The Spanish Ministry of Science and Innovation
• The European Research Council
• The Spanish Association Against Cancer
• The Generalitat de Catalunya
• The European Union's NextGenerationEU program
• The "la Caixa" Foundation
• Farmaindustria