Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations

Garay, Tamás and Molnár, Eszter and Juhász, Éva and László, Viktória and Barbai, Tamás and Dobos, Judit and Schelch, Karin and Pirker, Christine and Grusch, Michael and Berger, Walter and Tímár, József and Hegedűs, Balázs (2015) Sensitivity of Melanoma Cells to EGFR and FGFR Activation but Not Inhibition is Influenced by Oncogenic BRAF and NRAS Mutations. Pathology & Oncology Research. ISSN 1219-4956

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Abstract

BRAF and NRAS are the two most frequent onco- genic driver mutations in melanoma and are pivotal compo- nents of both the EGF and FGF signaling network. Accord- ingly, we investigated the effect of BRAF and NRAS onco- genic mutation on the response to the stimulation and inhibi- tion of epidermal and fibroblast growth factor receptors in melanoma cells. In the three BRAF mutant, two NRAS mutant and two double wild-type cell lines growth factor re- ceptor expression had been verified by qRT-PCR. Cell prolif- eration and migration were determined by the analysis of 3- days-long time-lapse videomicroscopic recordings. Of note, a more profound response was found in motility as compared to proliferation and double wild-type cells displayed a higher sensitivity to EGF and FGF2 treatment when compared to mutant cells. Both baseline and induced activation of the growth factor signaling was assessed by immunoblot analysis of the phosphorylation of the downstream effectors Erk1/2. Low baseline and higher inducibility of the signaling pathway was characteristic in double wild-type cells. In contrast, onco- genic BRAF or NRAS mutation did not influence the re- sponse to EGF or FGF receptor inhibitors in vitro. Our find- ings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activa- tion of growth factor receptor signaling. Since emerging mo- lecularly targeted therapies aim at the growth factor receptor signaling, the appropriate mutational analysis of individual melanoma cases is essential in both preclinical studies and in the clinical trials and practice.

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