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New route identified for tackling drug resistance in skin cancer cells

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A new therapeutic route for combatting treatment-resistant cancer has been identified with the discovery that melanoma cells fight anti-cancer drugs by changing their internal skeleton.

Researchers have found that melanoma cells fight anti-cancer drugs by changing their internal skeleton (cytoskeleton). This opens up a new therapeutic route for combatting skin and other cancers that develop resistance to treatment.

The team, led by Queen Mary University of London, UK, found that melanoma cells stop responding to both immunotherapies and drugs targeted at the tumour’s faulty genes (B-RAF or N-Ras mutations in the MAPK pathway) by increasing the activity of two cytoskeletal proteins – ROCK and Myosin II. They found that these molecules were key for cancer cell survival and resistance to these treatments.

…blocking the ROCK-Myosin II pathway not only reduces cancer cell growth, but also attacks faulty immune cells”

The molecules had previously been linked to the process of metastatic spread but not to the poor impact of current anti-melanoma therapies. This work points to a strong connection between metastasis and therapy resistance, the researchers said – confirming that the cytoskeleton is important in determining how aggressive a cancer is.

Tests in mice suggest that the therapy-resistant (or non-responding) tumours are effectively addicted to ROCK-Myosin II to grow. The team discovered that blocking the ROCK-Myosin II pathway not only reduces cancer cell growth, but also attacks faulty immune cells (macrophages and regulatory T cells) that are failing to kill the tumour; this action boosts anti-tumour immunity.

“We were very surprised to find that the cancerous cells used the same mechanism, changing their cytoskeleton, to escape two very different types of drugs,” said lead author Professor Victoria Sanz-Moreno, Professor of Cancer Cell Biology at Queen Mary. “In a nutshell, if you are a cancer cell, what does not kill you makes you stronger. However, their dependence on ROCK-Myosin II is a vulnerability that combination drug therapy tests on mice suggest we can exploit in the clinic by combining existing anti-melanoma therapies with ROCK-Myosin II inhibitors.”

“An important observation was finding increased Myosin II activity levels in resistant human melanomas, which suggests its potential as a biomarker of therapy failure,” added first author Jose L Orgaz, Research Fellow at Queen Mary’s Barts Cancer Institute. “Resistant melanomas also had increased numbers of faulty immune cells (macrophages and regulatory T cells), which could also contribute to the lack of response.”

The findings were published in Cancer Cell.

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