A study by the Institute for Research in Biomedicine of Barcelona (IRB Barcelona), based at the Barcelona Science Park, and the Cancer Research Center of Salamanca (CSIC, USAL, FICUS) shows that degrading the mutated KRAS protein PROTACs induces rapid tumor regression in mouse models of lung adenocarcinoma. The work identifies resistance mechanisms different from those observed with classic KRAS inhibitors, a finding of relevance for the arrival of the first KRAS degraders into clinical trials.

KRAS is one of the most frequently altered oncogenes in cancer and is mutated in approximately one-third of lung adenocarcinomas. For decades, it was considered undruggable until the recent approval of the first inhibitors targeting specific KRAS variants. However, these treatments often lose effectiveness over time due to the emergence of resistance. Now, this study, published in the journal Cancer Research, provides one of the first in vivo characterizations of how tumors develop resistance to therapies based on targeted protein degradation, a new generation of drugs that is already beginning to be tested in patients.

“KRAS inhibitors have represented a major breakthrough in the treatment of some cancers, but resistance remains a major problem. We are now entering a new phase, in which we can not only inhibit KRAS, but also make the tumor cell itself degrade it. The sequential use or even the combination of both pharmacological strategies could make the difference,” explains Dr. Cristina Mayor-Ruiz, researcher at IRB Barcelona and co-lead author of the study.

Making the cell itself destroy KRAS

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

Since there are still no PROTACs capable of directly degrading the KRAS^G12V mutation, the researchers designed an ingenious strategy: they genetically modified tumor cells to add a “molecular tag” or “tag” to the protein, allowing its elimination to be forced using new PROTACs designed and synthesized at IRB Barcelona, in collaboration with the group of Antoni Riera, which bind to this tag.

Gracias a ello, los investigadores pudieron destruir KRAS^G12V in vivo y observaron una marcada regresión tumoral. El modelo desarrollado no solo ha demostrado su utilidad en cáncer de pulmón, sino que es aplicable al estudio de terapias basadas en degradación dirigida frente a otros oncogenes y tipos de tumor.

“What we see is that tumor cells are extremely dependent on KRAS. When we eliminate the mutated protein, they stop proliferating and enter apoptosis, even in the absence of a functional immune system,” explains Dr. David Santamaría, researcher at the Cancer Research Center and co-lead author of the study.

Although treated tumors show greater infiltration of immune cells, experiments carried out in immunodeficient mice demonstrated that the initial regression depends mainly on mechanisms intrinsic to cancer cells, rather than on the action of the immune system.

The results also show that targeted degradation produces deeper and more durable antitumor responses than those usually observed with inhibitors.

Studying resistance to degraders in vivo

One of the most relevant findings of the study is the detailed analysis of how resistance to therapies based on targeted degradation appears in living tumors. The researchers observed that these mechanisms differ from those described for inhibitors.

Instead of mutating KRAS or reactivating classical tumor signaling pathways, in response to degraders cancer cells progressively alter the cellular machinery responsible for protein degradation, preventing KRAS from being effectively eliminated.

“It is a completely different form of resistance. The tumor continues to depend on KRAS, but learns to sabotage the system that destroys it,” notes Inés M. García-Pérez, co-first author of the study and predoctoral researcher at IRB Barcelona.

» Article of reference: Targeted KRASG12V degradation in vivo elicits lung adenocarcinoma regression with subsequent relapse from dysregulated proteolysis. Alberto Martín#,* , Inés M. García-Pérez#, Sonia San José, Pep Rojo, Carlos Riego-Mejías, Cristina Teodosio, Bárbara MG. Barbosa, Carolina Sánchez-Zarzalejo, Ignasi Folch-I-Casanovas, Antonia Odena Caballol, Sònia Jarió, Sara Hijazo-Pechero, Silvia M. Rodríguez-López, Rodrigo Entrialgo-Cadierno, Marie-Julie Nokin, José M. Muñoz-Félix, Diana Loa, Elizabeth Guruceaga, Camille Stephan-Otto Attolini, Chiara Ambrogio, Alberto Villanueva, Silvestre Vicent, Antoni Riera, David Santamaría* & Cristina Mayor-Ruiz*. Cancer Research (2026)

» Link to the news: IRB Barcelona website [+]