Researchers discover why melanoma develops resistance to treatment
Researchers from Massachusetts General Hospital (MGH) have discovered why melanoma develop resistance to therapies targeting BRAF / MEK pathway growth. New findings provide a better understanding of the mechanisms underlying melanoma resistance to treatment. It seems that BRAF inhibition alters metabolic activity in cancer cells and this change promotes resistance to treatment.
Melanoma is one of the most aggressive cancers, with a 5-year survival rate of less than 10%. Treatment of choice consists of surgical excision which is completed by radiotherapy, chemotherapy, immunotherapy, etc.. David E. Fisher, MD, PhD, chief of Dermatology at Massachusetts General Hospital (MGH), said they were surprised to learn that melanoma cells treated with vemurafenib, which is a BRAF inhibitor, changes the way cell produce energy. He added that BRAF inhibitors is a major step forward in the treatment of melanoma, because it causes tumor to shrink in most patients, and this prolongs survival by several months. Unfortunately,in many patients relapse occur. It is therefore essential to find some strategies in order that these responses to treatment persist more. Most cases of melanoma occur due to mutations in the BRAF gene, which is why BRAF inhibitors are used to decrease tumor size. But the researchers found that when BRAF inhibitors are combined with drugs targeting MEK, which is involved in the same pathway of tumor growth, treatment response is stronger.
The most common way to convert glucose into energy consists of oxidative phosphorylation that occurs in mitochondria, some cellular organelles specialized in producing energy. But it seems that cancer cells are able to produce energy through another mechanism that does not involve the mitochondria. The research done by investigators at the MGH Cancer Center reveals that an increased activity of BRAF reduces the level of a transcription factor called MITF, which in turn leads to suppression of oxidative phosphorylation. Also, reduction of MITF level decreases the level of PGC1, which is a protein that regulates the proper functioning of the mitochondria. In contrast, melanoma cells treated with BRAF inhibitors have high levels of MITF, with increased oxidative phosphorylation and an increase in the number of mitochondria. Resistance to treatment with BRAF inhibitors occurs due to the switch to oxidative phosphorylation to supply the energy needed by cancerous cells.
Fisher, the Wigglesworth Professor of Dermatology at Harvard Medical School, said the research indicates that combined treatment with mitochondrial inhibitors could increase the effectiveness of BRAF inhibitors in melanoma: “Several small molecules that target mitochondrial metabolism have been identified by investigators here at the MGH and elsewhere, and laboratory investigations of specific combinations of BRAF inhibitors with mitochondrial antagonists are currently underway.”