Among cancer's molecular "most wanted" are TRK fusion proteins. Under normal circumstances, TRK proteins play an essential role in the development of the nervous system. But sometimes a chromosomal accident fuses part of the TRK gene to part of an entirely different gene, creating a hybrid protein that sends a constant signal telling cells to grow and divide.
"TRK fusions can be found in very different types of tumors, from infantile fibrosarcoma to lung cancer and colon cancer," explained Dr. Saurav Kumar, a postdoctoral fellow from the Nabet Lab in the Human Biology division. That broad reach has made them an attractive target for drug development, and many TRK fusion-driven cancers initially respond well to a class of drugs called TRK inhibitors. These drugs work like a key jammed into a lock, binding to the TRK fusion and preventing it from sending its growth signal. But cancer is a fast learner. Over time, the TRK fusion can acquire new mutations that prevent these drugs from binding, restoring the constant growth signal that drives cancer.
Rather than designing ever more powerful inhibitors, researchers are exploring the possibility of removing the cancer-causing protein entirely.
Every cell has an elaborate recycling system that continually identifies old, damaged, or unwanted proteins and marks them for disposal. A class of drugs known as PROTACs, short for proteolysis-targeting chimeras, hijacks this natural cleanup process. Structurally, PROTACs act like molecular bridges, with one end binding the target protein and the other end recruiting the cell's protein disposal machinery. Instead of just blocking a disease-causing protein, PROTACs tag it for destruction. “Traditional inhibitors can effectively block a protein’s function, but PROTACs remove the protein altogether,” explained Dr. Behnam Nabet. “That may offer several benefits like lower dosing requirements to shrink tumors or more durable responses for patients.”
The Nabet Lab is working to harness this strategy against some of cancer's most challenging targets. In a recent collaborative study led by Kumar, the team developed a new TRK-targeting PROTAC called JWJ-01-378. The work brought together researchers from the Nabet Lab, the Holland Lab in the Human Biology division, the Ferguson Lab at the University of California San Diego, and Seattle-based Talus Bioscience.
The new PROTAC rapidly eliminated TRK fusion proteins and shut down the cancer-driving signals they produce. But the researchers also discovered something equally important when they compared their molecule with an earlier PROTAC. The older compound unexpectedly destroyed additional proteins that healthy cells rely on, including one called GSPT1, which is essential for cell survival. JWJ-01-378 showed much greater selectivity, demonstrating that it’s possible to design an effective PROTAC that destroys the intended target while leaving other critical proteins untouched.
But the work is not finished. The current molecule cannot yet degrade TRK fusion proteins carrying resistance mutations that often emerge after treatment with existing TRK inhibitors. Developing degraders that overcome those resistance mutations is one of the team's next goals. As Kumar explained, "Ultimately, we aim to develop next-generation TRK degraders with improved pharmacological properties and translate these findings toward more effective and durable therapies for patients."
The broader approach of targeted protein degradation recently reached an important milestone. In May 2026, the first PROTAC therapy received FDA approval, demonstrating that this once experimental strategy can succeed in the clinic. As researchers continue to refine targeted protein degraders, they could offer a new way to tackle some of cancer's most difficult drug targets.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium Members Drs. Behnam Nabet and Eric Holland contributed to this research. This research was supported by the Cellular Imaging Shared Resource of the Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium.
The spotlighted research was funded by the Hartwell Innovation Fund, the National Science Foundation, and the National Institutes of Health.
Kumar S, Jiang J, Donald-Paladino MS, Chen J, Gutierrez A, Federation AJ, Szulzewsky F, Holland EC, Ferguson FM, Nabet B. 2026. Development of PROTACs for targeted degradation of oncogenic TRK fusions. RSC Chemical Biology. DOI: 10.1039/D6CB00008H
Science Spotlight writer Thamiya Vasanthakumar is a postdoctoral research fellow in the Campbell Lab at Fred Hutch. As a structural biologist, she uses cryogenic electron microscopy (cryoEM) to visualize the molecular structures of receptors found on the surface of immune cells.