Selumetinib shows promise against aggressive RDEB skin cancer cells
Study: Experiments in mouse models resulted in reduced tumor growth
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Selumetinib, a drug that’s approved to treat certain types of neurological tumors, may be an effective treatment for skin cancers in people with recessive dystrophic epidermolysis bullosa (RDEB), according to a new study.
Researchers found that selumetinib treatment killed cancer cells in dish-based tests, while experiments in mouse models showed it reduced tumor growth.
The study, “Transcriptome-guided drug repurposing identifies selumetinib for an aggressive epithelial cancer,” was published in the Journal of Investigative Dermatology.
Selumetinib approved in US, Europe to treat nerve tumors
RDEB is a genetic disorder that affects the skin and the mucosa and is associated with a high risk of squamous cell carcinoma (SCC), a type of skin cancer. Available treatment options for SCC tumors associated with RDEB, referred to as RDEB-SCCs, are limited and have variable efficacy.
Selumetinib is an oral therapy approved in the U.S. and Europe under the brand name Koselugo for the treatment of neurofibromatosis type I, a genetic condition that causes tumors to grow on nerves and changes in skin color. The therapy works to reduce the activity of the mitogen-activated protein kinase (MAPK) pathway, a molecular signaling pathway that plays a key role in driving the abnormal growth of certain cancer cells.
In 2022, a team of scientists in Austria conducted a computational analysis of genetic activity in cells from RDEB-SCC tumors. That computer-based assessment indicated that the MAPK pathway is highly active in these skin tumors and suggested selumetinib as a promising therapeutic option. Repurposing approved drugs, rather than designing a new treatment from scratch, is generally cheaper and faster because the therapy’s safety profile is already understood.
“Drug repurposing offers an efficient route to the clinics owing to known safety profiles and reduced development times and costs,” the scientists said.
In lab tests, therapy diminished cells’ capacity to invade other tissues
In this study, the researchers conducted tests in lab models of RDEB-SCC to help provide proof-of-concept data to support their computational tests.
The scientists first tested selumetinib on RDEB-SCC cells in dishes. They found that the treatment reduced cell viability and diminished the cells’ capacity to migrate and invade other tissues — traits that are key to cancer cells’ ability to metastasize, or spread to other parts of the body.
The treatment also modulated the activity of immune-related proteins in the cancer cells. Specifically, it decreased levels of programmed death-ligand 1, a protein that cancer cells use to evade the immune system. At the same time, the treatment increased levels of major histocompatibility complex-I, a protein that immune cells interact with to investigate cells for suspicious activity. Collectively, these changes would be expected to increase the immune system’s ability to eliminate the tumor cells.
Our findings support selumetinib as a promising therapeutic for RDEB-SCCs and highlight the potential of computational repurposing in accelerating drug development for rare diseases.
The researchers then tested selumetinib in mice with implanted RDEB-SCC tumors. They found that the treatment reduced tumor growth by roughly twofold, with no apparent safety issues for the animals.
“Our findings support selumetinib as a promising therapeutic for RDEB-SCCs and highlight the potential of computational repurposing in accelerating drug development for rare diseases,” the researchers concluded.
Although the lab data support selumetinib as a potential anti-cancer agent in RDEB-SCC, the researchers noted that this medication is known to cause skin issues as a common side effect. While these are usually manageable, the fact that people with RDEB already have an underlying skin disorder highlights a need for caution. As a practical consideration, the researchers said that other inhibitors of the MAPK pathway, especially formulations that can be administered topically as a cream or ointment applied to the skin, may be better suited for use in RDEB patients.
