Cancer Diagnostics / Lab News

BRAF positive metastatic malignant melanomas resistant to inhibitor treatment

BRAF positive metastatic malignant melanomas resistant to inhibitor treatmentThis large study has found that BRAF positive metastatic malignant melanomas develop resistance to drugs which target the BRAF/MEK growth pathway through a change in metabolism. Findings will be published in Cancer Cell and suggest a plan which may improve the effectiveness of targeted therapies which are currently available.

David E. Fisher, MD, PhD, Chief of Dermatology at Massachussetts General Hospital (MGH) and a co-corresponding author of the Cancer Cell paper, says they were surprised to find that melanoma cells treated with BRAF inhibitor vemurafenib drastically change how they produce energy to stay alive. Whilst current BRAF inhibitor treatment offers major improvement as it shrinks tumours and extends survival by several months, patients do relapse eventually. A need therefore exists to improve the magnitude and durability of these responses.

In approximately half of the cases of malignant melanoma, the most deadly form of skin cancer, mutations in the BRAF gene drive the tumour growth. Researchers have found that treatments which block BRAF activity stops tumour growth, but only temporarily. Combining this BRAF inhibitor with an additional drug which targets the MEK protein, in the same growth pathway, extends the anti-tumour response.

Cells use glucose to make energy via a process called oxidative phosphorylation and relies heavily on the activity of mitochondria. Many cancer cells however, use an alternative mechanism that produces ATP (the energy compound) without the use of mitochondria. The MGH researchers discovered that elevated BRAF activity in BRAF positive melanoma cells suppresses oxidative phosphorylation by reducing expression of a transcription factor called MITF. Reduced production of MITF reduces the levels of PGC1α, a protein that regulates the generation and function of mitochondria. However, melanoma cells treated with a BRAF inhibitor showed elevated MITF activity, in addition to an increased expression of oxidative phosphorylation genes along with more mitochondria. By changing to oxidative phosphorylation to supply energy, the tumour cells improved their ability to survive, even against BRAF inhibitor treatment.

Dr Fisher, Wigglesworth Professor of Dermatology at Harvard Medical School, said “These findings suggest that combination treatment with mitochondrial inhibitors could improve the efficacy of BRAF inhibitors in malignant melanoma”. Investigators are currently looking into combinations of BRAF inhibitors with mitochondrial antagonists.



Randox Laboratories provide a number of arrays to test for tumour markers like CEA and AFP used in the detection and monitoring of various cancers.  For more information, visit the Biochip Immunoassays section of the website.

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