The advent of targeted small-molecule therapies, a decade ago, revolutionized the treatment of metastatic melanoma, provided that tumors carry the mutations to respond to these therapies. However, despite the brilliant initial response that can be seen in the majority of patients, most will relapse even after the initial brilliant responses. These relapses are caused by permanent “dormant” cells, which do not respond to treatment. A team from the University of Geneva (UNIGE) and the University Hospitals of Geneva (HUG) showed that these cells express a protein called HuR. By deciphering the mechanism of this insufficient expression and targeting it with an enzyme inhibitor, this team succeeded in reducing the therapeutic resistance of all melanoma cells. These results have been published in Biochemistry and biophysical research in communicationOpening new therapeutic approaches against metastatic melanoma and other types of solid cancers.
Skin cancer is one of the most dangerous types of skin cancer. Possibly very aggressive, they develop from melanocytes, the cells responsible for skin pigmentation. The primary tumor can be superficial with a good prognosis when removed, and it can also be deeper and become metastatic, that is, migrate to other organs of the body.
Over the past 10 years, thanks to the advent of so-called small-molecule-targeted therapies — drugs that block a precise mechanism within the tumor to fight it — half of the metastatic melanomas that bear a genetic fingerprint that makes them sensitive to these drugs can be effectively treated, and sometimes even eliminated. “Despite these impressive initial responses, 80% of patients will experience a recurrence, and these recurrences often occur in the same initially affected sites,” explains Rastine Merat, a researcher in the Department of Medicine at UNIGE Medical School and chair of the UNIGE Department of Medicine. The HUG Cutaneous Oncology Unit.
The protein is involved in the regulation of cell division
This phenomenon is called “adaptive resistance”: some cancer cells adapt to the drugs used to combat them and lead to a recurrence of the disease. This occurs even when the metastases – and thus the cells that make these tumors – seem to have completely disappeared. “This is explained by the persistence of small remnants of so-called ‘sleeper’ malignant cells that conventional radiology instruments cannot detect, after treatment,” says Rustin Mirat. “The peculiarity of these cells, in addition to being invisible, is that they multiply slowly. This property helps cells escape treatment, even during the initial treatment.”
Previous research has shown that in slow-proliferating cells, a protein that regulates, among other things, the expression of several genes that control cell division – the HuR protein – is not sufficiently expressed. This is in contrast to rapidly proliferating cells in which this protein is highly expressed. In a research work published in 2019, Rustin Mirat and his team demonstrated the link between insufficient expression of this protein and the ability of melanoma cells to resist targeted therapy. In their latest research, they discovered a specific mechanism involved in the insufficient expression of this protein in “dormant” cells that can be targeted with drugs.
Inhibition of enzymes to prevent recurrence
“In cells, messenger RNAs play a central role in protein production. In the minority of cells in which HuR is insufficiently expressed, we have found that HuR mRNAs are trapped by some other proteins. This is at least one of the mechanisms leading to insufficient HuR expression. “. By using a chemical compound to inhibit two kinases – two enzymes – implicated in this mechanism, the UNIGE team was able to block the insufficient expression of HuR, reducing the ability of all melanoma cells to resist treatment.
“The great difficulty in carrying out this work was working on this type of cell, which is difficult to detect and analyze due to their small number and the fact that the state of insufficient expression of HuR protein is dynamic and reversible at any time for any cells; that is, at any time the cells can start itself in replication and reversal to a high state of expression of this protein”, explains the researcher. To do this, “We overexpressed this protein in melanoma cells. This allowed us to make the mechanisms of play more easily detectable.” This discovery opens new avenues in the treatment of skin cancer, but not only. “Melanoma is a typical cancer: if we understand it, we can understand many other solid cancers,” Rustin Mirat explains.
For the researcher and his team, “the next step will be to encourage the pharmaceutical industry to improve inhibitors of specific kinases, to improve their stability and bioavailability – something that pharmaceutical drug companies know how to do nowadays in a very systematic way, at least for this type of goal,” he concludes. Rustin Mirat.