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

Abstract

BRAF and NRAS are the two most frequent oncogenic driver mutations in melanoma and are pivotal components of both the EGF and FGF signaling network. Accordingly, we investigated the effect of BRAF and NRAS oncogenic mutation on the response to the stimulation and inhibition 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 receptor expression had been verified by qRT-PCR. Cell proliferation 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, oncogenic BRAF or NRAS mutation did not influence the response to EGF or FGF receptor inhibitors in vitro. Our findings demonstrate that the oncogenic mutations in melanoma have a profound impact on the motogenic effect of the activation of growth factor receptor signaling. Since emerging molecularly 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.

Phenytoin enhances the phosphorylation of epidermal growth factor receptor and fibroblast growth factor receptor in the subventricular zone and promotes the proliferation of neural precursor cells and oligodendrocyte differentiation

“…In adult neural stem cells, EGF and FGF-2 are important regulators of cell proliferation, migration and survival (Gritti et al, 1999;Doetsch et al, 2002;Gonzalez-Perez & Quinones-Hinojosa, 2010;Galvez-Contreras et al, 2012a). Increasing evidence also indicates that EGF and FGF act synergistically and regulate gene amplification in a great variety of cancers (Garay et al, 2015). Hence, EGFR and FGFR activation triggers a myriad of cellular events that may alter brain homeostasis.…”

Uncarboxylated Osteocalcin Induces Antitumor Immunity against Mouse Melanoma Cell Growth

“…In contrast, GlaOC enhanced the phosphorylation levels of many kinds of RTKs, particularly EGFR, ErbB2, ErbB3, ErbB4, macrophage-stimulating protein receptor, PDGFRα, PDGFRβ, TrkC, and VEGFR3. These nine RTKs are growth factors belonging to the families of EGFR 39 , MET proto-oncogene 40 , PDGFR 41 , 42 , Trk 43 , and VEGFR 44 , which are closely related to tumor progression of melanoma 38 , 43 , 45 - 51 . These data were consistent with the results of proliferation assays, although whether the phosphorylation is a direct effect or a secondary effect has not been established.…”

Perturbation biology links temporal protein changes to drug responses in a melanoma cell line

“…There are many available drugs that specifically inhibit EGFR and are expected to decrease EGFR-pY992 as a proxy of downstream action, for example the drugs lapatinib [14], gefinitib, and erlotinib. Inhibitors of EGFR alone did not have a strong anti-proliferative effect in melanoma cell lines [15].…”

“…The combined effect is not inhibited by gefitinib since gefitinib is selective for EGFR. There are other drugs that inhibit both EGFR and HER2 (e.g., erlotinib or peletinib) that are more efficient in melanoma cell lines [15]. The third reason has to do with translatability from model predictions to available drugs.…”