Targeting the Ubiquitin Machinery to Rewire KRAS-Driven Cancers

One of the most stubborn problems in modern oncology is the KRAS gene. Mutated versions of this small signaling protein drive some of the deadliest human malignancies, including pancreatic, colorectal and lung cancers, and for decades they were considered essentially undruggable. Although recent years have delivered a wave of KRAS inhibitors directed against the most common mutation, the G12C variant, the broader family of KRAS-driven tumors still lacks effective targeted options, and resistance emerges rapidly even in patients who initially respond. Now, a comprehensive review published in Experimental & Molecular Medicine argues that a major part of the answer may lie not in blocking KRAS directly, but in exploiting a different layer of cellular regulation altogether: the ubiquitin–proteasome system, and in particular the enzymes known as deubiquitinases.

The ubiquitin–proteasome system is the cell’s principal machinery for controlled protein destruction. Small ubiquitin tags are attached to target proteins through an enzymatic cascade involving activating enzymes, conjugating enzymes and ligases, and proteins carrying specific ubiquitin chains are recognized and degraded by the proteasome, a barrel-shaped proteolytic complex. Because the system governs the abundance of virtually every regulatory protein in the cell, including tumor suppressors, cell-cycle drivers and signaling components, it has long been considered a rich source of therapeutic targets. The clinical success of proteasome inhibitors in multiple myeloma, and more recently the explosive growth of targeted protein degrader technologies, have confirmed that manipulating protein turnover can be a powerful anti-cancer strategy.

Deubiquitinases, or DUBs, sit at the opposite end of this pathway. Rather than attaching ubiquitin, these proteases remove it, cleaving ubiquitin chains from substrates or editing the architecture of the chains themselves. In doing so, DUBs stabilize proteins that would otherwise be destroyed, fine-tune signaling complexes and recycle ubiquitin for reuse. The human genome encodes roughly one hundred DUBs, distributed across several mechanistically distinct families, including cysteine proteases of the USP, UCH, OTU and MJD classes and metalloproteases of the JAMM family. Their activities touch nearly every cellular process, and a growing body of evidence shows that many DUBs are dysregulated in cancer, where they act as oncogenes or tumor suppressors depending on the context.

The review’s central thesis is that DUBs are deeply intertwined with KRAS biology, and that this connection creates therapeutic openings that conventional approaches have overlooked. KRAS operates as a molecular switch, cycling between an active, GTP-bound state and an inactive, GDP-bound state, and transmitting signals downstream through the RAF–MEK–ERK and PI3K–AKT pathways. Each stage of this circuit is buffered by ubiquitin-dependent regulation. Ubiquitin ligases such as the CUL3 complex, which recognizes active KRAS through the adaptor protein calcoco-2, can ubiquitinate KRAS and promote its degradation, acting as a built-in brake on signaling. DUBs that remove ubiquitin from KRAS or from components of its downstream pathways effectively remove that brake, amplifying and prolonging the oncogenic signal. Conversely, inhibiting the right DUB could restore the degradation of mutant KRAS or sensitize tumor cells to existing inhibitors.

Several individual DUBs have emerged as particularly compelling nodes in this network. The USP family member USP11, for example, has been reported to stabilize KRAS by removing its ubiquitin marks, thereby sustaining ERK signaling in KRAS-mutant cells. USP21 and USP22 have similarly been implicated in supporting KRAS-driven transcriptional programs, partly through their effects on chromatin regulators and signaling intermediates. On the downstream side, DUBs such as USP9X, USP5 and CYLD regulate the stability of RAF, MEK and ERK pathway components as well as NF-kappaB signaling, shaping both the intensity of the oncogenic output and the inflammatory milieu of the tumor microenvironment. Because these enzymes act at multiple points in the circuit, they offer a way to modulate KRAS signaling even when direct inhibition of the protein itself is technically or clinically difficult.

This matters enormously for the translational landscape. The G12C inhibitors sotorasib and adagrasib demonstrated that covalent drugs can reach mutant KRAS in the recessed pocket of its switch-II region, yet their impact is limited to the roughly one in eight KRAS-mutant tumors that carry the G12C alteration, and resistance through pathway reactivation, tissue plasticity and drug-tolerant persister cells develops within months. Approaches that work through protein turnover are intrinsically broader. A DUB inhibitor, or a degrader built on DUB biology, would not need a druggable pocket on KRAS itself; it would only need to shift the balance of the degradation machinery. The review highlights this as a route toward tumors carrying non-G12C mutations such as G12D, G12V and Q61, which together account for the majority of KRAS-driven cancers and remain without approved targeted therapies.

The therapeutic logic also extends to combination strategies. Preclinical studies indicate that degrading or destabilizing KRAS, whether through ligase recruitment or through DUB inhibition, can cooperate with upstream and downstream blockade, for instance pairing proteasome-directed approaches with SHP2 inhibitors, MEK inhibitors or ERK inhibitors to collapse the adaptive signaling networks that tumors deploy under treatment pressure. In resistant tumors where KRAS amplification or bypass signaling restores ERK output, lowering the total pool of KRAS protein could re-sensitize cells to doses of pathway inhibitors that are otherwise survivable. The review frames DUB targeting as a complementary pillar to the degrader boom: while molecular glue compounds and PROTACs recruit ubiquitin ligases to tag targets for destruction, DUB inhibitors would work by removing the enzymes that protect oncogenic proteins from destruction.

The challenges, however, are substantial, and the review is candid about them. DUBs are proteases, and designing selective inhibitors for cysteine protease active sites has proven difficult, with many early compounds suffering from broad reactivity and poor pharmacology. Redundancy is a second obstacle: multiple DUBs can often compensate for one another, meaning that single-agent inhibition may produce modest effects unless the dominant node in a given tumor is correctly identified. There is also the problem of context. The same DUB can act as an oncogene in one cancer and a tumor suppressor in another, so patient stratification and biomarker development will be essential. Finally, because the ubiquitin system regulates a vast range of non-cancerous processes, including immune signaling and DNA repair, systemic toxicity must be carefully evaluated.

To navigate these difficulties, the review outlines several priorities for the field. Better structural biology and cryo-electron microscopy of DUB-substrate complexes could reveal allosteric and protein-protein interaction surfaces that are more drug-friendly than catalytic sites. Proteomic approaches that map the ubiquitin landscape of KRAS-mutant tumors, increasingly accessible through ubiquitin-remnant mass spectrometry, could identify which DUBs are genuinely rate-limiting in which genetic backgrounds. And emerging chemical modalities, including covalent fragments targeting non-catalytic cysteines, targeted protein degraders and PROTAC-inspired molecules that eliminate DUBs themselves rather than merely inhibiting them, may open doors that classical enzyme inhibitors could not. The authors argue that systematic functional genomics, using CRISPR screens in panels of KRAS-mutant cell lines, will be key to converting the growing catalog of DUB-KRAS interactions into a validated target hierarchy.

The significance of this synthesis lies in its reframing of a familiar problem. Rather than treating KRAS as a target to be occupied, it treats the KRAS-mutant cell as a network whose protein economy can be rewired. The ubiquitin–proteasome system provides the levers, and deubiquitinases, once obscure players in basic cell biology, are now positioned as actionable points of intervention in some of medicine’s most intractable cancers. If the chemical and biological hurdles can be overcome, the coming years could see DUB-directed therapies enter clinical trials for pancreatic, lung and colorectal cancers, offering new hope to patients whose tumors have eluded the first generation of KRAS drugs.

Subject of Research: Therapeutic targeting of deubiquitinases in the ubiquitin–proteasome system to treat KRAS-driven cancers.

Article Title: Rewiring KRAS-driven cancers through the ubiquitin–proteasome system: therapeutic opportunities with a focus on deubiquitinase

Article References: Lee, Y., Hwang, S., Shin, H., Choi, K., Seo, S., Kim, H., Yang, J. S., Kim, Y. J., Kim, Y.-M., & Song, E. J. (2026). Rewiring KRAS-driven cancers through the ubiquitin–proteasome system: therapeutic opportunities with a focus on deubiquitinase. Experimental & Molecular Medicine. https://doi.org/10.1038/s12276-026-01837-6

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01837-6

Keywords: KRAS, deubiquitinase, ubiquitin-proteasome system, targeted cancer therapy, protein degradation, RAS signaling, proteasome inhibitors, oncology, USP family, drug resistance, Rewiring, KRAS-driven