Melanoma is the most aggressive and lethal type of skin cancer. Drugs called BRAF inhibitors, used either alone or more successfully in combination with MEK inhibitors (termed BRAF-MEK inhibitors), have revolutionised the treatment of melanoma that has spread (metastasised) but the cancer often becomes resistant to the drug(s), causing the treatment to fail. Genetic mutations can result in cancer cells evading treatment but genetic factors alone cannot explain all the drug resistance observed. Understanding more about other mechanisms of resistance would allow the design of new drugs to improve the likelihood of treatment success.
Érica Aparecida de Oliveira and colleagues from the groups of Professors Silvya Stuchi Maria-Engler (University of Sao Paulo, Brazil) and Colin Goding (Ludwig Oxford) set out to investigate non-genetic causes of resistance to BRAF and BRAF-MEK inhibitors. They focussed on an enzyme called TOP1 which relaxes DNA supercoiling – a process required for DNA replication in cancers. TOP1 inhibitors are already used in the clinic to treat colorectal and ovarian cancers.
Reported in Pharmacological Research, the team discovered that the levels of TOP1 are raised during progression from benign cells to metastatic melanoma and correlate with invasive growth. However, TOP1 levels are decreased in BRAF inhibitor- and BRAF-MEK inhibitor-resistant cells, and pharmacological inhibition of TOP1 decreased invasion markers only in BRAF-MEK inhibitor-resistant cells. These results demonstrate the potential involvement of TOP1 in melanoma progression and resistance but question the use of TOP1 inhibitors as a treatment for BRAF/BRAF-MEK inhibitor-resistant melanoma.
Image credit: Skin cancer cell. Annie Cavanagh. Attribution-NonCommercial 4.0 International (CC BY-NC 4.0)