Read time: 3 minutes.
RET proteins are a type of receptor tyrosine kinase—an important group of signaling molecules in healthy cells. When RET proteins are turned “on” and “off” in healthy cells, they control the function of other proteins. This cascading effect allows the cells to manage important cellular functions such as cell growth through protein signaling pathways.
When specific changes (such as mutations or fusions) occur in RET proteins, they can become hyperactive, disrupting many important functions in the cell including growth, proliferation, and cell death, that lead to the development of cancer.
Targeting RET+ Cancer
RET-driven cancers are rare. RET-fusions are found in approximately 1% of non-small cell lung cancer diagnoses, but they can occur in many parts of the body, including the thyroid and the prostate. Two RET-specific inhibitors, pralsetinib and selpercatinib, have been approved by the US Food and Drug Administration (FDA) to treat RET-driven metastatic non-small cell lung cancer and RET-driven metastatic thyroid cancer.
These treatments have been effective for many patients, and people continue to benefit from these therapies. However, the tumors eventually learn to evade treatment and begin to grow again. This drug resistance can develop for different reasons, and researchers are working to understand more about these processes.
Supporting Cutting-Edge RET+ Research
As the leading nonprofit funder of lung cancer research, LUNGevity has strategically invested more than $50 million in lung cancer research. Our ongoing commitment to creating a world where no one dies from lung cancer is evident in our robust portfolio of research projects.
One of the projects funded by LUNGevity, in partnership with RETpositive—a patient-driven nonprofit that aims to improve the quality of life and life expectancy of RET-positive cancer patients—supports an exciting new approach to overcoming drug resistance in RET-driven cancers.
Justin Drake, PhD, at the University of Minnesota, is the recipient of the 2024 RETpositive/LUNGevity Translational Research Award for RET-positive Cancer.
Dr. Drake’s work uses innovative technology to use the cell’s natural ability to break down and recycle proteins the cell doesn’t need anymore. This natural process, called protein degradation, relies on tagging the proteins which need to be recycled. By attaching a string of ubiquitin tags to a protein, the cell can send any ubiquitin-tagged protein to the proteasome (the cell’s “trash can”) to be broken down.
Dr. Drake wants to send cancer-driving RET-fusion and RET-mutated proteins to the proteasome to be degraded.
Using PROteolysis Targeting Chimeras (PROTACs), his research team is building a new drug with three segments:
- A binding site specific for RET protein
- A linker molecule
- E3 ubiquitin ligase to tag RET with ubiquitin molecules.
This approach of targeting key proteins for degradation through ubiquitination is currently being tested for other proteins in different cancer types with promising results. These studies have provided proof-of-concept for this approach which is likely to offer a long-lasting effect through lower doses (and therefore less side effects for patients).
The success with immunotherapy in treating cancer has shown us the benefits of building on the body’s natural ways of doing things. That is the beauty of this research. This forward-looking approach has the potential to revolutionize the way we treat patients with RET-driven cancers of all types, including lung cancer. And we are proud to partner with RETpositive to support this incredible work.
-Upal Basu Roy, PhD, MPH, Executive Director of Research at LUNGevity
Dr. Basu Roy recently moderated a live webinar with Dr. Drake and Emily Walthall of RETpositive to provide those living with lung cancer first-hand access to this exciting research as it unfolds.
Watch the recording below for:
- The role of research in treating RET-positive lung cancer
- Introduction to proteomics
- Understanding the benefits of PROTACs
- Dr. Drake’s research plans and timeline
- Applications to other types of oncogene-driven cancer
- …and so much more
For more information about RET+ lung cancer, visit the LUNGevity Rare Mutations Patient Gateway.
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