Blocking a survival mechanism in melanoma


Tuesday, 03 December, 2019


Blocking a survival mechanism in melanoma

The effectiveness of current treatments for melanoma could be improved by using approaches that wipe out the ‘survival system’ of cancer cells, according to a study conducted by UK researchers and published in the journal Nature Communications.

There are around 16,000 new melanoma skin cancer cases in the UK every year, with late-stage melanoma evolving rapidly to resist treatment. This is because cancer cells can rely on various ‘survival proteins’ to stay alive despite the effect of treatment, and scientists have so far been unable to pinpoint which of these survival proteins are used by melanoma cells.

Researchers from the Babraham Institute and the Cancer Research UK Cambridge Institute have now discovered that melanoma cells rely on a protein called MCL1, which is critical for the cells to survive when they are exposed to standard MEK and BRAF inhibitor drugs, such as trametinib or vemurafenib. They then studied an investigational compound from biopharma company AstraZeneca, an MCL1 antagonist called AZD5991, and used it in the lab against models of melanoma.

The team showed that by blocking MCL1, AZD5991 inactivated the backup survival system within melanoma cells. Combining AZD5991 with a treatment like vemurafenib had a ‘double whammy’ effect against cancer cells, eliminating them more effectively.

This drug combination also worked in late-stage melanoma tumours, derived from patients and grown in mice. In these mice, combinations of vemurafenib and AZD5991 reduced the size of tumours, sometimes almost completely, and slowed their growth compared to standard treatment alone. However, used alone, AZD5991 had no effect in these models.

Patients with these aggressive tumours may be given a different type of drug called an ERK inhibitor; although these drugs are still undergoing clinical trials and not widely available yet, it already seems that melanoma could evolve rapidly to resist them. Future clinical trials could look at whether blocking MCL1 at the same time as giving an ERK inhibitor could halt the evolution of these late-stage tumours from becoming resistant.

“This study has demonstrated that melanoma cells are addicted to the MCL1 protein for survival, but only when they are treated with the existing melanoma drugs,” said lead researcher Dr Matthew Sale, from the Babraham Institute. “By targeting both vulnerabilities at the same time we can kill melanoma cells, causing greater inhibition of tumour growth over a longer time period.”

Image credit: ©stock.adobe.com/au/Damian Gretka

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