Throwing cancer-driving proteins in the cellular trash

When cancer-driving proteins resist various treatments, Northwestern University scientists have uncovered a new solution. Don't fight them - throw them in the cellular trash.

In a new study, scientists developed a protein-like polymers (PLPs) capable of grabbing proteins and directing them to the cell's waste-disposal machinery. From there, the proteins are degraded and disposed, triggering cancer cell death.

The study will be published on Tuesday (Feb. 24) in the journal Nature Communications.

As a proof-of-concept, the researchers tested a specific class of these PLPs, called HYDRACs (HYbrid DegRAding Copolymers), on two particularly problematic proteins: MYC and KRAS. Both proteins drive uncontrolled growth in many cancers and, despite decades of drug development efforts, resist most treatment strategies and common types of drugs such as small molecules and antibodies.

In cellular cultures, the HYDRACs selectively sought and destroyed MYC and KRAS proteins across multiple cancer cell lines. In animal tumor models, the MYC-targeted HYDRACs accumulated in tumors, reduced cancer cell proliferation and stalled tumor growth. With this early success, the scientists are hopeful their new platform could be adapted to target a wide range of proteins to fight cancer and other protein-related diseases.

"MYC and KRAS drive a huge fraction of human cancers - often aggressive ones - and effective drugs for them are extremely limited," said Northwestern's Nathan Gianneschi, who led the study. "We developed a one-step polymer chemistry solution. The protein mimetic polymers engage disordered proteins and bring them together with the cellular machinery that degrades it. That had never been done before, and it proved effective against some of the most challenging targets in cancer biology."

An expert on polymer chemistry, Gianneschi is the Jacob and Rosaline Cohn Professor of Chemistry at Northwestern's Weinberg College of Arts and Sciences, a professor of materials science and engineering and biomedical engineering at the McCormick School of Engineering and a professor of pharmacology at Northwestern University Feinberg School of Medicine. He also is a member of the International Institute for Nanotechnology, Querrey Simpson Institute for Regenerative Engineering, Chemistry of Life Processes Institute and the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

Taking out the trash with two hands

Rather than blocking a protein's activity, HYDRACs belong to a growing class of therapies known as targeted protein degraders, which work by marking harmful proteins for destruction. Existing degraders typically use small molecules, but scientists struggle to design these for "undruggable" proteins like MYC and KRAS. Undruggable proteins often lack well-defined binding pockets, so the small molecules have nowhere to latch onto. Without a good "handle," drugs cannot bind tightly enough to function.

HYDRACs take a different approach. Each polymer displays multiple copies of target-binding peptides that recognize proteins of interest and molecular signals that summon the cell's protein-degradation machinery. This strategy takes advantage of the cell's natural built-in quality-control system, which seeks out old, damaged or unnecessary proteins and degrades them.

Each PLP essentially has two hands. One hand grabs the protein, and the other hand grabs the cell's 'dust bin.' It's literally like picking up a piece of trash off the ground, grabbing the waste basket and putting them near each other."

Nathan Gianneschi, Northwestern University

Instead of needing a perfect pocket, HYDRACs grabs disease-causing proteins and brings them to the cell's disposal machinery - eliminating the protein entirely. HYDRACs work even when the proteins lack defined pockets, which normally prevents binding.

Dragging 'kicking and screaming' proteins

As a proof of concept, Gianneschi and his team first focused on MYC, a protein commonly found in breast, colon, lung, prostate, liver, blood and ovarian cancers. In cancer cells, HYDRACs selectively degraded the MYC protein, shut down MYC-driven genes and triggered cancer cell death. In a mouse model with MYC-driven tumors, HYDRACs halted tumor growth without significant side effects.

To demonstrate the flexibility of the system, the team reprogrammed the platform to target KRAS, another notoriously difficult cancer protein. Occurring in about 25% of human cancers, KRAS-driven cancers include pancreatic and colorectal. While current treatments against KRAS do exist, those work only for a narrow subset of specific mutations and rapidly lose effectiveness over time. 

"In the last few years, researchers have developed small molecule drugs that target specific KRAS mutations," Gianneschi said. "In many cases, patients became resistant to the drugs as the cancer mutates to resist treatment. That's because cancer cells work incredibly hard to evade therapies, especially when they're hitting a protein target at the core of the tumor's survival."

HYDRACs, however, selectively and successfully degraded KRAS proteins in cancer cells, including proteins carrying different mutations.

"That's the advantage of the multivalent, polymer-based degrader strategy we have developed," Gianneschi said. "It doesn't matter if a protein mutates, it's still going into the bin. KRAS can be actively changing, kicking and screaming all the way to the trash can, but all we need to do is destroy the whole protein. This is a potentially powerful way to foil the cell which cannot easily mutate away from your drug."

What's next

While the current study focused on cancer, Gianneschi plans to adapt HYDRACs to target proteins related to neurodegenerative, inflammatory and metabolic diseases. Northwestern spinout Grove Biopharma has licensed the intellectual property for the technology and is advancing it as part of its Bionic Biologics platform, accelerating translation toward therapeutic development.

"By demonstrating this platform with two completely different undruggable proteins, we think it might work to open up other targets," Gianneschi said. "It's a new way to think about targeted treatments. It's not just about finding the perfect small molecule. It's about designing systems that can work with the cell to eliminate many different harmful proteins altogether."

The study, "Heterobifunctional proteomimetic polymers for targeted degradation of MYC and KRAS," was supported by the Willens Center for Nano Oncology, International Institute of Nanotechnology and the Liz and Eric Lefkofsky Innovation Research Award.