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Characterizing the clinical relevance and the mechanism underlying TRIB2-mediated drug resistance to MEK inhibitiors in the context of melanoma

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Fighting drug resistance in cancer patients

A pioneering EU-funded project has shed new light on why some cancer patients develop resistance to treatments. The findings could lead to new therapies that resensitise cancerous cells to anticancer drugs, saving lives.

Health

Malignant melanoma is a highly aggressive cancer that arises from the transformation of melanocytes, the pigment-producing cells in human skin. Although malignant melanoma accounts for just 5 % of all skin cancers, it is responsible for 80 % of all skin cancer deaths. Most worryingly, incidences of metastatic melanoma have increased over the past three decades, with a mortality rate that continues to rise faster than almost all other cancers. Although two recent treatment options – immunotherapy and targeted therapy – have improved clinical outcomes, the development of resistance after initial responses has limited their efficacy. “A major hurdle to successful treatment continues to be resistance to therapy,” explains TRIBBLES project coordinator Wolfgang Link, a researcher at the Institute for Biomedical Research Alberto Sols in Spain. “We wanted to better understand the role of certain genes in order to overcome this resistance.”

Overcoming therapeutic resistance

The TRIBBLES project, supported by the Marie Skłodowska-Curie Actions programme, and coordinated by the University of Algarve in Portugal, built on a previous discovery made by Link and his team. A novel oncogene (a gene that has the potential to cause cancer) in melanoma was identified, called TRIB2. Link found that the expression of TRIB2 correlated with the tumour stage of melanoma, and conferred resistance to anticancer drugs. “Our observations of TRIB2 triggered our interest in exploring the molecular mechanisms underlying this behaviour,” he says. “We thought that this could lead to new strategies to pharmacologically target these mechanisms.” This was the key objective of the TRIBBLES project. The team set about achieving this goal by generating new tools to analyse the role of TRIB2 in therapy resistance. “We selected two independent cell clones in which TRIB2 had been depleted by using CRISPR/Cas9 gene editing technology,” adds Link. “These cell lines were used to analyse changes in gene expression, depending on the level of TRIB2 protein.” These trials helped to confirm that alterations in gene expressions are involved in the mechanism of TRIB2-mediated therapy resistance. The next stage was to identify possible pharmacological strategies capable of reversing TRIB2-mediated changes, in order to overcome therapeutic resistance. “We were able to show that two naturally occurring alkaloids – harmine and piperlongumine – can inverse the gene expression profile produced by TRIB2 and sensitise cancer cells to anticancer drugs,” says Link. “Both agents were found to promote the nuclear translocation of FOXO proteins (tumour-suppressing proteins) and induce the transcription of FOXO target genes.”

New cancer-fighting drugs

Understanding the cellular mechanisms that underly therapeutic resistance is critical to developing new drugs capable of resensitising cancer cells to anticancer drugs. The TRIBBLES project has made a vital contribution in this regard and opened the door to identifying chemical compounds that might inhibit TRIB2 activity and overcome TRIB2-mediated drug resistance. Early findings suggest that harmine, piperlongumine or similar compounds could be used to overcome TRIB2-mediated therapy resistance in cancer patients. “We are currently exploring the use of drugs that impact on the expression or activity of TRIB2, in combination with anticancer therapeutics,” notes Link. “We are also exploring the importance of our findings for other tumour entities, such as brain tumours.”

Keywords

TRIBBLES, cancer, melanoma, skin, TRIB2, therapeutic, CRISPR, tumour, immunotherapy

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