Degrading mutant KRAS protein induces greater lung cancer regression

KRAS is one of the oncogenes most frequently altered in cancer, mutated in approximately one-third of lung adenocarcinomas. For decades, it was considered undruggable, until the recent approval of the first inhibitors against specific KRAS mutants. However, these treatments often lose efficacy over time due to the emergence of resistance. Now, this new study explores a different pharmacological strategy based on inducing tumor cells to degrade mutant KRAS themselves.

The study, led by IRB Barcelona and the Centro de Investigación del Cáncer (CSIC, USAL, FICUS), demonstrates that destroying the mutant KRAS protein, rather than merely blocking its activity, induces greater lung cancer regression in preclinical mouse models.

Published in Cancer Research, the study also provides one of the first in vivo characterizations of how tumors develop resistance to targeted protein degradation therapies based on PROTACs, a new modality of drugs which has already reached clinical approval.

KRAS inhibitors have brought about a massive shift in the treatment of certain cancers, but resistance remains a major hurdle. We are now entering a new era where we can not only inhibit KRAS but also induce its degradation within cancer cells. Sequentially or even concurrently combining both pharmacological strategies could make a significant difference."

Dr. Cristina Mayor-Ruiz, researcher at IRB Barcelona and co-lead author of the study

Inducing tumor cells to degrade KRAS

Unlike classic inhibitors that block a protein's activity, targeted protein degradation strategies utilize molecules known as PROTACs to make the cell destroy the tumor protein itself.

Since PROTACs capable of directly degrading the KRAS^G12V mutation are currently unavailable, the researchers devised an ingenious strategy: they added a "molecular tag" to the protein. This allowed them to force its degradation using novel PROTACs-designed and synthesized at IRB Barcelona in collaboration with Antoni Riera's group-that specifically engage this tag.

Using this approach, the researchers successfully degraded KRAS^G12V in vivo, observing a pronounced tumor regression. This newly developed model has not only proven useful for studying lung cancer but also provides a framework for investigating targeted protein degradation therapies against other cancer-relevant proteins and tumor types.

What we observe is that lung cancer cells are extremely dependent on mutant KRAS. When we degrade the mutated protein, they stop proliferating and undergo apoptosis, even in the absence of a functional immune system."

Dr. David Santamaría, researcher at the Centro de Investigación del Cáncer and co-lead author of the study

Although treated tumors show increased immune cell infiltration, experiments conducted in immunodeficient mice demonstrated that the initial regression depends primarily on mechanisms intrinsic to the cancer cells rather than immune system activity.

The results further demonstrate that targeted KRAS^G12V degradation produces more profound and durable antitumor responses than those observed with conventional inhibitors.

Investigating resistance to degraders in vivo

One of the study's most significant findings is the detailed analysis of how resistance to targeted protein degradation therapies emerges in living tumors. The researchers observed that these resistance mechanisms are distinct from those previously described for traditional inhibitors.

Instead of mutating KRAS or reactivating classical oncogenic signalling pathways in response to the degraders, the cancer cells progressively alter the cellular machinery responsible for protein elimination, thereby preventing KRAS from being effectively degraded.

 "It is a fundamentally distinct resistance mechanism. The tumor continues to rely on KRAS, but it essentially learns to sabotage the machinery meant to destroy it," points out Inés M. García-Pérez, co-first author of the study and PhD researcher at IRB Barcelona.

This work stems from a collaborative effort between the groups led by Dr. Cristina Mayor-Ruiz at IRB Barcelona and Dr. David Santamaría at the Centro de Investigación del Cáncer (CSIC, USAL, FICUS). The study also involved key contributions from researchers at 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.

This work was supported by funding from the Spanish Ministry of Science and Innovation (State Plan for Scientific and Technical Research and Innovation), the European Research Council (ERC), the Spanish Association Against Cancer (AECC), the Generalitat de Catalunya (AGAUR and TRIP-Clinics), the European Union's NextGenerationEU program, the "la Caixa" Foundation, and Farmaindustria.