Underlying Mechanism of BRAF-inhibitor Resistance May Lead to New Melanoma Treatments

Researchers have identified several mechanisms that may cause BRAF inhibitor resistance in melanoma patients.

It is estimated that between 40% and 50% of metastasizing melanomas have a BRAF mutation, which enables tumor growth. Although these patients can be treated with a BRAF inhibitor in combination with MEK inhibitor, they end up developing treatment resistance even though their initial response was a positive one.

In the new study, researchers from the Medical University of Vienna wanted to identify these resistance mechanisms, with the next steps involving the delay or prevention of resistance. Researchers used mass spectrometry (shotgun proteomics) to identify and characterize proteins from human cells.

This method involves proteins in complex mixtures being digested, while the resulting peptides are separated by liquid chromatography.

“We were able to show that resistance to the BRAF inhibitor is associated with elevated expression of the lysosomal compartment (spherical vesicular cell organelles), with increased cell binding and with morphological changes in the cells, from spherical to spindle-shaped,” said researcher Verena Paulitschke. “As cell models, we used cells with induced resistance and primary cell systems, in which similar signatures were identified. It was then possible to correlate the expression of proteins (which were upregulated in the resistant cells) with poor progression free survival using tissue sections or sera of melanoma patients.”

Using this resistance profile, researchers were able to demonstrate the efficacy of resveratrol derivatives M8, which is a naturally occurring polyphenol mostly found in grapes.

“New technologies such as ‘shotgun proteomics’ have enabled us to make a mechanistic analysis of innovative therapeutic approaches,” Paulitschke said. “Using these strategies, it has been possible to obtain new insights into the underlying mechanism of resistance to BRAF inhibition and, based on that, we might be able to develop new rational therapeutic concepts and predictive and pharmacodynamics biomarkers.”