PLK1 potential target in RDEB-linked skin cancer, analysis shows

PLK1 blockers being tested as possible treatments for solid tumors

Steve Bryson, PhD avatar

by Steve Bryson, PhD |

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The enzyme polo-like kinase 1 (PLK1) may be a potential therapeutic target for squamous cell carcinoma (SCC) associated with recessive dystrophic epidermolysis bullosa (RDEB), according to an analysis of tumor tissue from an RDEB patient with recurring cancer.

The gene that encodes PLK1 was almost seven times more active in tumor tissue than in the patient’s skin, the analysis showed.

Inhibitors of PLK1, an enzyme that participates in cell cycle regulation, are under investigation in clinical trials to treat solid tumors. The findings might be clinically relevant because of that, the researchers said.

Their study, “Accelerated Aging and Microsatellite Instability in Recessive Dystrophic Epidermolysis Bullosa-Associated Cutaneous Squamous Cell Carcinoma,” was published in the Journal of Investigative Dermatology.

The team, led by researchers at Brigham & Women’s Hospital and Boston Children’s Hospital, wrote that they detected dysfunctional DNA repair mechanisms in tumor tissue as well as signs of accelerated aging as “factors potentially contributing to the aggressive nature and early onset of RDEB SCC.”

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Research is scarce as both conditions are rare

All types of DEB are caused by mutations in the COL7A1 gene, which lead to a deficiency in functional type VII collagen, a connective tissue protein that helps connect the layers of skin. Without this protein, the skin of RDEB patients is extremely fragile, with widespread blistering, chronic inflammation, and scarring.

RDEB patients are at risk of developing SCC, an aggressive skin cancer with limited treatment options. Because both conditions are rare, studies on the development of SCC in RDEB patients are scarce.

The researchers conducted a genetic analysis of tissue samples collected from a 32-year-old woman with severe RDEB and seven recurrences of SCC. Their goal was to understand the underlying biological mechanisms of RDEB-associated SCC and identify potential therapeutic targets or treatments.

Blisters at birth prompted a skin biopsy and genetic testing, which found a different mutation in each of her COL7A1 genes. Clinical examination was consistent with generalized-severe RDEB.

Between ages 22 and 31, the woman developed seven SCC lesions in chronic wounds or blisters on both legs. Six of these were removed by surgery, and one was treated with a series of medications. She also developed a serious infection of the bone next to the SCC lesions and underwent a below-the-knee amputation.

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Increase seen in gene that encodes PLK1 enzyme

Blood samples and tissue from a skin blister and the SCC lesion were collected at the time of the first biopsy and subjected to whole genome sequencing (WGS) and RNA sequencing.

WGS examines the entire DNA sequence from each tissue type to look for SCC-associated mutations. RNA sequencing assesses gene activity by measuring the levels of different messenger RNA (mRNA), molecules that carry the genetic information to make a protein. Higher levels of a specific mRNA reflect a more active gene and more protein being produced.

As expected, the two COL7A1 mutations found at birth were detected in the blood, skin, and tumor. One mutation led to a shortened version of type VII collagen, which would be rapidly degraded, and the other disrupted the proper processing of COL7A1 mRNA.

In the SCC samples, RNA sequencing identified 1,285 genes with higher activity and 4,570 genes with lower activity than the skin. Among those with higher activity, there was a 6.56 times increase in the gene that encodes the PLK1 enzyme in the tumor over the skin.

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Tests show difference in patient’s age and skin age

WGS examination detected mutations in SCC tumor samples that were different from mutations in the skin, including those in pathways called NOTCH, p53, SWI/SNF, Hippo, Cell Stress, and Ras MAPK/PI3K.

The team then discovered high microsatellite instability (MSI) in the tumor. MSI reflects a cell’s inability to repair errors that spontaneously occur during DNA replication, which can increase mutations and accelerate cancer growth.

“High MSI status of the patient tumor might provide additional treatment options such as immunotherapy, which was approved by the [U.S. Food and Drug Administration] for patients with MSI-high tumors,” the researchers wrote.

We demonstrate the promise of bridging the gap between genomic research and clinical applications for developing tailored therapies for patients with rare genetic disorders such as RDEB.

Experiments revealed a significant difference between the patient’s age, 26, and the biological age of her RDEB skin, 57. And when she was 27, her RDEB SCC skin indicated a biological age of 77. No differences in chronological and biological age were detected in control samples of healthy skin and psoriasis skin without lesions.

“These results potentially implicate accelerated biological aging in RDEB-associated skin disease and SCC development,” the researchers wrote.

“We demonstrate the promise of bridging the gap between genomic research and clinical applications for developing tailored therapies for patients with rare genetic disorders such as RDEB,” they wrote.