Scientists hypothesize new mechanism for destroying cancer-causing protein

Original article can be found at the APS website.

RAS proteins function as on/off switches in pathways controlling cell growth and proliferation. Mutated RASs keep the pathways permanently activated, leading to conditions such as cancer and Noonan syndrome. A protein called Leucine Zipper-like Transcription Regulator 1 (LZTR1) regulates cellular levels of RAS by promoting RAS’s destruction. However, LTZR1 is itself prone to mutations, disrupting its ability to bind and degrade RAS and causing diseases such as Noonan syndrome and Schwannomatosis.

Now, a team of scientists has revealed how LZTR1 recognizes and binds RAS to label it for destruction. Furthermore, their crystal structures reveal three types of mutations in LZTR1 that disrupt RAS binding. Their findings support development of a molecular glue that could help bind LZTR1 and oncogenic RAS, promoting reduction of the cancer-causing protein.

The team used the resources of the Advanced Photon Source (APS), a U.S. Department of Energy (DOE) Office of Science user facility at DOE’s Argonne National Laboratory. The work was published in Science in September 2025.

There are more than 150 different proteins in the RAS superfamily. They act as switches by cycling between an active state, in which they bind an organic molecule called Guanosine Triphosphate (GTP), and an inactive state, in which GTP is broken down to Guanosine diphosphate (GDP). The balance of inactive and active RAS is tightly controlled in the cell by several different processes. One process is the targeted degradation of RAS proteins by LZTR1, but does it prefer some RAS proteins over others?

To answer that question, the research team employed isothermal titration calorimetry to investigate how normal LZTR1 and RAS proteins bind. It was already known that LZTR1 recognizes RAS only in its inactive state, but the team found that LZTR1 preferred certain forms of RAS over others: RIT1 bound best, then MRAS, then KRAS, a form of RAS which is often mutated in cancer.

The scientists were able to crystallize structures of LZTR1 with MRAS and RIT1, but they were unable to form crystals with KRAS. To circumvent this problem, they mutated KRAS to look more like RIT1. This mutation stabilized the complex enough to form crystals. Using the Northeastern Collaborative Access Team (NE-CAT) facilities at APS beamline 24-ID-E, the scientists collected data of LZTR1 bound to inactive RIT1 at 2.95 Å resolution. Inactive MRAS at 2.80 Å resolution and mutant KRAS at 3.30-Å resolution were collected at the Diamond Light Source in the UK, with support from APS during their shutdown and upgrades.

Though it was known that LZTR1 only engaged RAS proteins in their inactive state, no one knew why. The team answered that question by solving their crystal structures. Structural details revealed that RAS proteins have two switches, whose conformations are dictated by which nucleotide—GTP or GDP—is bound. With GDP, the switches are looser and engage with LZTR1. With GTP, the switches are in a conformation that clashes with LZTR1 and prevents binding and their degradation.

Like all proteins, LZTR1 was susceptible to mutations. Whereas mutated KRAS primarily causes cancer, mutated LZTR1 primarily causes Noonan syndrome and Schwannomatosis. The crystal structures gave the scientists another avenue for exploration: did disease-causing mutations affect LZTR1’s affinity with RAS, and if so, how?

They analyzed 25 LZTR1 disease-causing mutants and found that 22 failed to bind RIT1. Using the structures, they identified three types of mutations, each a different cause for non-binding. The first type either broke interactions keeping RIT1 and LZTR1 together or introduced clashes with RIT1. The second type destabilized the loops of LZTR1 where RIT1 bound. The third destabilized the hydrophobic core of LZTR1 by introducing a charged amino acid. These LZTR1 mutations severely weaken or prevent binding of RIT1, leading to less degradation and an overabundance of RIT1, which causes disease.

Mutating KRAS to look more like RIT1 led to another key finding: increasing the affinity of the RAS protein to LZTR1 led to greater degradation. If better affinity led to increased degradation, would there be a way, the researchers wondered, to increase the affinity between oncogenic KRAS and LZTR1, to target cancer-causing KRAS for destruction? Oncogenic KRAS behaves as a broken switch, predominately in the active state, though it still cycles through the inactive state. Could that brief moment of time present a window of opportunity for LZTR1 to bind and target it for destruction? The scientists hypothesized that developing a sticky molecular “glue” might do the trick.

The proposal is hypothetical, and not all KRAS mutants would be targetable. Nevertheless, a sticky molecular glue does represent a strategy to overcome resistance to drugs that are currently on the market. Using it to bind LZTR1 to oncogenic RAS proteins represents a hopeful next step in the fight against life-numbing diseases. – Judy Myers

See: S. Dharmaiah¹, D. Bonsor¹, S.P. Mo², A. Fernandez-Cabrera², A.H. Chan¹, S. Messing¹, M. Drew¹, M. Vega², D.V. Nissley¹, D. Esposito¹, P. Castel², D.K. Simanshu¹, “Structural basis for LZTR1 recognition of RAS GTPases for degradation,” Science 389 6765 1112-1117 (2025)  DOI: 10.1126/science.adv7088

Author affiliations: ¹Frederick National Laboratory for Cancer Research; ²NYU Grossman School of Medicine.

This work is based upon research conducted at the NE-CAT beamlines, which are funded by the National Institute of General Medical Sciences of the National Institutes of Health (NIGMS/NIH grant P30 GM124165). The Eiger 16M detector on 24-ID-E is funded by the NIH Office of Research Infrastructure Programs [ORIP High-End Instrumentation (HEI) grant S10 OD021527]. This research used the resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under contract no. DE-AC02-06CH11357, and was supported by an agreement between the Advanced Photon Source and the Diamond Light Source, the UK’s national synchrotron science facility, located at the Harwell Science and Innovation Campus in Oxfordshire, where the work was performed under proposal AU34315-3 and by a grant from National Cancer Institute of the NIH (NCI grant R01 CA279171 to P.C.) and the Department of Defense Neurofibromatosis Research Program (grant HT94252310248 to S.M.). We thank the NYU Proteomics laboratory, which is supported in part by NYU Langone Health and the Perlmutter Cancer Center support grant P30 CA016087 from NCI, for quantitative MS. This project was also funded in part with federal funds from the NCI/NIH (contract 75N91019D00024). The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, and the mention of trade names, commercial products, or organizations does not imply endorsement by the US Government.

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