Scientists at IRB Barcelona have achieved what once seemed impossible: making lung cancer cells destroy themselves by degrading the mutant proteins that fuel their growth. In a landmark study published in Cancer Research, researchers led by Dr. Cristina Mayor-Ruiz have demonstrated that this novel approach—inducing tumor cells to degrade mutant KRAS rather than merely blocking it—produces more profound and durable regressions in preclinical mouse models than conventional treatments.
KRAS mutations are among the most common genetic alterations in cancer, occurring in roughly one-third of lung adenocarcinomas. For decades, the mutation was considered undruggable, making it one of the most frustrating obstacles in cancer research. Recent approvals of the first KRAS inhibitors marked a breakthrough, yet these drugs often lose their effectiveness as tumors develop resistance. The Barcelona team's strategy represents a fundamentally different approach: instead of fighting KRAS from the outside, they are compelling cancer cells to eliminate the protein from within.
The breakthrough hinges on a class of molecules called PROTACs, a novel drug modality that has already received clinical approval. Since PROTACs capable of directly degrading the specific KRASG12V mutation did not yet exist, the researchers engineered an ingenious workaround. They added a molecular tag to the mutant KRAS protein, then designed and synthesized new PROTACs—developed in collaboration with Antoni Riera's group at the institute—that target this tag and trigger the cell's own degradation machinery. When they tested this approach in living tumors, the results were striking: pronounced tumor regression followed.
What makes this discovery particularly powerful is how thoroughly the cancer cells depend on mutant KRAS. When the protein is degraded, lung cancer cells stop proliferating and undergo apoptosis—programmed cell death—even in mice with no functional immune system. Dr. David Santamaría, co-lead author from the Centro de Investigación del Cáncer, explains 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." Although treated tumors showed increased immune cell infiltration, experiments in immunodeficient mice proved that the initial tumor regression depended primarily on mechanisms intrinsic to the cancer cells themselves.
Perhaps equally important is what the study revealed about how tumors develop resistance. The researchers conducted one of the first detailed in vivo characterizations of resistance to targeted protein degradation therapies. They discovered something unexpected: instead of mutating KRAS or reactivating the oncogenic signaling pathways that typically allow tumors to escape traditional inhibitors, cancer cells took a different approach. The tumor cells progressively altered their cellular machinery—the very machinery responsible for protein elimination—essentially learning to sabotage the system designed to destroy KRAS.
This distinction could prove crucial for future treatment strategies. Dr. Mayor-Ruiz emphasizes that combining KRAS inhibitors with these new degradation therapies "sequentially or even concurrently" could make a significant difference. The framework developed by the Barcelona team extends beyond lung cancer, offering a blueprint for investigating targeted protein degradation against other cancer-relevant proteins and tumor types. As resistance mechanisms continue to challenge cancer treatments worldwide, understanding how tumors evade these new therapies may be just as important as the therapies themselves.