Functionality of drug resistance in melanoma decoded

(Vienna, 15^th April 2015) A research group at the University Clinic of Dermatology at the MedUni Vienna is on the trail of melanoma resistances to cancer drugs. The identification of the mechanisms leading to resistance to BRAF inhibitors in metastasizing melanomas harbouring the V600E BRAF mutation is a success, which may result in more effective treatments in future.

The human BRAF gene produces a protein (B-Raf) which, as an important component of the RAS-RAF signalling pathway, plays a part in the growth and survival of cells. Mutated forms can cause this signalling pathway to become overactive leading to uncontrolled cell growth and cancer. It is estimated that such mutations are found in approximately 60 percent of all melanomas.

Identifying the origins of resistances
Although BRAF inhibitors, such as Vermurafenib, administered for treatment achieve outstanding clinical response rates in patients with metastasizing melanoma with the V600E BRAF mutation, nevertheless early resistance is common.

The study published in the journal "Molecular Cancer Therapeutics" demonstrates in a melanoma model with resistance to the BRAF inhibitor Vemurafenib how these resistance mechanisms may function: thus, there occurs an increased expression of the lysosomal compartment, an increased cell adhesion and epithelial-mesenchymal transition with typical morphological change.
Based on the proteome profile it was possible, in an initial approach, to successfully predict the effectiveness of a resveratrol derivative, M8.

"We have gained new insights into the underlying mechanism of resistance to BRAF inhibition. Based on this, new rational treatment concepts and predictive and pharmacodynamic biomarkers might be developed," explains study leader Verena Paulitschke from the Clinical Department of General Dermatology and Dermato-Oncology at the University Department of Dermatology at the MedUni Vienna, "the identification of the pathomechanisms of drug resistance and the development of effective therapeutic alternatives are the main challenges in melanoma research and are of highclinical relevance."


Proteomics provide an insight into pathophysiological processes
Despite intensive research efforts to shed light on the resistance mechanisms of BRAF inhibition, in particular at genetic level, the breakthrough has still not been achieved. Here a decisive role is played by the high plasticity and heterogeneity of the melanoma, which allows tumour cells to adapt to biological processes. Proteomics make it possible to gain an insight into the active pathophysiological processes and to generate protein signatures based on this.
The proteome analyses were conducted at the Institute of Analytical Chemistry of the University of Vienna in collaboration with Christopher Gerner and his research group. The cell cultures were generated by Walter Berger and his group at the Comprehensive Cancer Center (CCC) of the MedUni Vienna and the Vienna General Hospital.


Service: Molecular Cancer Therapeutics
The study "Vemurafenib Resistance Signature by Proteome Analysis Offers New Strategies and Rational Therapeutic Concepts" was published in the journal Molecular Cancer Therapeutics (impact factor: 6.1) by Verena Paulitschke et al. (Rainer Kunstfeld’s Study Group) of the Clinical Department of General Dermatology and Dermato-Oncology (chairman Hubert Pehamberger) of the MedUni Vienna. An electron microscope image of the melanoma cells analysed has now appeared as the cover picture of the journal Molecular Cancer Therapeutics in its March edition (March 2015; 14 (3)).