Oral squamous cell carcinoma, or OSCC, is a formidable enemy in canine medicine. Oral tumors affect an estimated half a percent of dogs over their lifetimes and account for about six percent of the canine cancer burden, with OSCC making up roughly nineteen percent of all oral tumors. The disease is locally invasive, growing through multiple anatomical planes of the jaw and surrounding tissue, causing severe pain, difficulty eating, and in some cases pathological fractures of the bone. Up to twenty percent of affected dogs show signs of metastasis by the time they are diagnosed. Left untreated, it is deadly.

The current standard of care is blunt: wide-margin surgical excision. While surgery is highly effective when non-metastatic tumors are completely removed, with very low recurrence rates, it is also highly invasive and invariably disfiguring. Roughly thirty percent of dogs have difficulty eating after surgery, and larger operations bring longer healing times, greater postoperative pain, and higher risks of complications. Radiation is occasionally used for tumors that cannot be surgically removed or as an adjunct to surgery, but the fundamental treatment paradigm has not changed in decades, even as researchers have made major strides in understanding the molecular machinery driving the disease.

That machinery centers on the RAS signaling pathway. Recent studies have shown that canine OSCC displays highly activated RAS signaling compared with healthy gingival tissue, a finding confirmed by gene set enrichment analysis comparing tumor samples with normal tissue. RAS is a small GTPase that, when activated by extracellular signals binding to receptors on the cell surface, launches a cascade of molecular events that ultimately drive cell growth and survival. The most important arm of this cascade for tumor growth is the RAS-RAF-MEK-ERK pathway, which ends with ERK initiating the gene transcription programs that keep a tumor expanding. The question facing the Cornell team was whether this pathway could be pharmacologically attacked in a way that would benefit dogs whose tumors are driven by a variety of different upstream mutations.

The answer they settled on was trametinib, a small molecule that inhibits MEK1 and MEK2, the kinases sitting in the middle of the pathway. Trametinib binds to the non-phosphorylated form of MEK in an allosteric pocket near the ATP binding site, blocking its catalytic activity and its ability to activate ERK. Crystal structures show the drug does more than simply plug the pocket: it also prevents BRAF from binding to MEK and appears to stabilize MEK’s association with KSR, the kinase suppressor of RAS, further reducing MEK’s affinity for BRAF. Crucially, the team chose trametinib precisely because it works on wildtype, unmutated proteins. Since RAS itself is rarely mutated in canine OSCC and BRAF mutations appear in only about a third of tumors, drugs like sotorasib, which bind only mutant RAS, would have left most patients out in the cold. Trametinib, by contrast, targets the pathway regardless of what triggered its activation.

The drug also came with a reassuring safety pedigree. It is FDA-approved in humans for BRAF-mutant melanoma and non-small cell lung cancer, typically alongside the BRAF inhibitor dabrafenib. A phase I trial in eighteen dogs had already demonstrated an acceptable safety profile over nine weeks of treatment, and the European Medicines Agency reported the drug was well tolerated in beagles over thirteen weeks and fully eliminated within about seven days. Its high oral bioavailability in both species meant it could be given at home, avoiding the stress and expense of repeated hospital visits.

The trial itself was designed with a do-no-harm philosophy. Twenty dogs with histologically confirmed OSCC were enrolled between October 2023 and February 2025, after approval by Cornell’s Institutional Animal Care and Use Committee and with informed consent from owners. Dogs received daily oral trametinib at doses escalating from 0.015 to 0.035 milligrams per kilogram, with examinations every two weeks including caliper tumor measurements, complete blood counts, and serum chemistry panels. Full tumor staging with contrast-enhanced computed tomography was performed at the start, around day 28, and around day 56, and tumor volumes were measured from CT slices by a board-certified veterinary radiologist. Response was categorized using veterinary RECIST criteria, and any dog showing progressive disease was removed immediately and returned to standard care. Because the typical two-week wait before surgery would not be compromised, owners could try the drug without sacrificing the earliest opportunity for curative excision.

The results were remarkable in some patients. One dog achieved a complete response, with no tumor detectable by CT, and five achieved partial responses, giving an overall response rate of thirty percent. Five more dogs had stable disease, meaning fifty-five percent of the cohort derived clinical benefit. Some tumors responded with startling speed: two dogs’ tumors had shrunk to less than one cubic centimeter after just two weeks of treatment, and in five dogs the mean volume reduction at the first post-treatment evaluation was forty-five percent. In two responsive patients, bone window CT scans showed actual bone regrowth at the tumor site, visible at 28 and 56 days after treatment began, a sign of genuine tissue healing rather than mere tumor shrinkage. In some cases the visible portions of tumors became difficult or impossible to identify by external inspection.

Safety data were equally encouraging. No high-grade adverse events were detected in any dog, though about thirty percent of owners reported transient flatulence that resolved on its own. Bloodwork showed mostly grade 1 and grade 2 abnormalities that were typically no worse than pre-treatment values. The only two grade 3 events, elevated alkaline phosphatase in two dogs, were preceded by grade 2 liver enzyme elevations present before treatment began, suggesting preexisting liver pathology unrelated to the drug. No dog was removed from the study or had its dose modified because of side effects, and no neutropenia was observed. Notably, a prior phase I study had flagged hypertension and proteinuria in some dogs at similar doses, but the Cornell team did not observe owner-reported behaviors consistent with those conditions, though blood pressure and urinalysis were not directly monitored.

The most scientifically compelling finding emerged when tumors were stratified by BRAF mutational status. Seven dogs carried tumors harboring the BRAF p.V595E mutation, the canine equivalent of the human V600E mutation, and these responded dramatically better than BRAF wildtype tumors. Among BRAF-mutant cases, one dog had a complete response and four had partial responses, for a seventy-one percent objective response rate and a mean volume reduction of seventy-one percent in responding tumors. Wildtype tumors, by contrast, showed a mean reduction of only seven percent among responders, and total clinical benefit in that group was just eight percent. The difference was statistically significant at p equals 0.01. Because BRAF genotyping requires only simple PCR amplification and Sanger sequencing, the authors suggest it could readily be implemented by diagnostic laboratories to identify dogs most likely to benefit. The team recommends a starting dose of 0.030 milligrams per kilogram daily while cautioning that dose-response analyses were underpowered. Limitations remain, including the absence of an untreated control group, the lack of long-term recurrence and survival data, and the small cohort size, but the study establishes trametinib as a safe, orally available neoadjuvant option that can shrink tumors in about a third of dogs before surgery, and in the majority of those whose tumors are BRAF-mutant, with results visible in as little as two weeks.

Subject of Research: Clinical trial of the MEK inhibitor trametinib for treating oral squamous cell carcinoma in dogs

Article Title: Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma

Article References: Katt, W. P., Balkman, C. E., Byron, M., Carney, P. C., Chrostek, E., Drozd, M. E., Duhamel, G. E., Fiani, N., Hume, K. R., King, A. L., Sylvester, S. R., Todd-Donato, A. B., Winokur, C. E., Wright, A. L., & Peralta, S. (2025). Clinical application of the MEK inhibitor trametinib in dogs with oral squamous cell carcinoma. Veterinary Oncology, 2(1), Article 31. https://doi.org/10.1186/s44356-025-00042-3

Image Credits: AI Generated

DOI: 10.1186/s44356-025-00042-3

Keywords: trametinib, MEK inhibitor, oral squamous cell carcinoma, canine cancer, BRAF mutation, RAS signaling, veterinary oncology, targeted therapy, clinical trial, neoadjuvant treatment, Cornell University, dog health

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