Potential New Drug for Melanoma Destroys, Rather than Inhibits, Cancer-Causing Proteins

Grantee: Craig Crews, PhD
Institution: Yale University in New Haven, Connecticut
Area of Study:
Cancer Drug Discovery
Grant Term: 1/1/2019 to 12/31/23

"To develop a new drug to treat melanoma, we’re investigating “the use of a new technology developed in my lab that approaches drug development in a different way. Instead of the traditional pharmaceutical paradigm that focuses on blocking the function of a disease-causing protein, our new approach focuses on enlisting the cell's own quality-control machinery to eliminate the rogue protein. By hijacking the cellular processes that normally remove proteins, we can simply make disease-causing proteins 'go away'.”—Craig Crews, PhD

The Challenge: The BRAF gene has the code to produce the BRAF protein, which helps ensure cells to grow and die normally. BRAF is an oncogene, meaning that when it’s mutated, it has the potential to cause normal cells to become cancerous. The proteins made by oncogenes are oncoproteins.

One mutation in the BRAF gene, called the V600E variant, is in about 60% of melanomas. This mutation is likely caused by exposure to ultraviolet radiation from the sun.

Several FDA-approved drugs target this genetic defect and inhibit it, and they have been successful in increasing survival of people with melanoma. But eventually, the cancer cells become resistant to the drug, meaning they are no longer responding to it, and are continuing to grow. These treatment-resistant melanomas are sometimes called “not pharmaceutically vulnerable” or “undruggable.”

There’s also a need for drugs to target the other—more than 300—genetic changes in the BRAF gene in melanomas.

The Research: Craig Crews, PhD, an ACS Research Professor is using a drug-design strategy that he co-developed about 20 years ago that’s been called a game changer in drug development. The technology is called Proteolysis Targeting Chimera, or PROTAC. Its strategy is to harness the cell’s waste disposal system, which acts like mini garbage trucks, removing unneeded or damaged proteins. Instead of simply inhibiting mutant proteins as other drugs do, PROTAC drugs help to destroy and remove them.

For melanoma, the studies done so far have shown that PROTACs work by tagging the V600E protein variant with another protein called ubiquitin, which is in almost all tissues and helps regulate other proteins. Ubiquitin acts as a red flag, prompting the cell to digest or degrade it.

Another benefit is that, unlike oncoprotein inhibitors that need to bind to their target over an extended period of time to work well, PROTACs follow more of a ‘hit and run’ strategy: relatively short exposures to therapeutic doses of PROTACs result in complete elimination of the target. The shape of PROTACs also allows them to access difficult to reach oncoproteins.

In a recently published paper, Crews and his lab team studied how their investigational PROTAC drug candidate, based on the current melanoma drug Keytruda (vemurafenib), successfully targeted BRAF mutants in numerous cancer cell lines (cancer cells taken from patients and grown in the lab). In addition, they studied their lead PROTAC in mice with transplants of human melanoma cells and found that the PROTAC degraded many different mutations of BRAF in the tumors.

In these lab studies, they found that their vemurafenib-based PROTAC drug was better than vemurafenib alone at targeting and eliminating BRAF V600E as well as other BRAF oncoprotein variants without negatively affecting normal BRAF proteins.

Why it Matters: Crews’ study demonstrates that PROTAC technology can be used to target difficult-to-treat oncoproteins such as mutant forms of BRAF. The authors showed that they could tune the specificity of their PROTAC in multiple ways, making it a versatile approach for targeting and degrading other oncoproteins in the future. For instance, his approach may lead to treatments for other cancers that have mutated BRAF proteins, which include 10% of colorectal cancers, 10% of non-small cell lung cancer, and 100% of hairy cell leukemia.