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Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas.

ABSTRACT: BRAF mutations are frequent in cutaneous melanomas, and BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients. However, acquired drug resistance can occur rapidly and tumor(s) often progresses thereafter. Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial. In this study, we developed BRAFi-resistant melanoma cell lines and found that metastasis-related epithelial to mesenchymal transition properties of BRAFi-resistant cells were enhanced significantly. Upregulation of EGFR was observed in BRAFi-resistant cell lines and patient tumors because of demethylation of EGFR regulatory DNA elements. EGFR induced PI3K/AKT pathway activation in BRAFi-resistant cells through epigenetic regulation. Treatment of EGFR inhibitor was effective in BRAFi-resistant melanoma cell lines. The study demonstrates that EGFR epigenetic activation has important implications in BRAFi resistance in melanoma.

SUBMITTER: Wang J

PROVIDER: S-EPMC4307785 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas.

Wang Jinhua J Huang Sharon K SK Marzese Diego M DM Hsu Sandy C SC Kawas Neal P NP Chong Kelly K KK Long Georgina V GV Menzies Alexander M AM Scolyer Richard A RA Izraely Sivan S Sagi-Assif Orit O Witz Isaac P IP Hoon Dave S B DSB

The Journal of investigative dermatology 20140922 2

BRAF mutations are frequent in cutaneous melanomas, and BRAF inhibitors (BRAFi) have shown remarkable clinical efficacy in BRAF mutant melanoma patients. However, acquired drug resistance can occur rapidly and tumor(s) often progresses thereafter. Various mechanisms of BRAFi resistance have recently been described; however, the mechanism of resistance remains controversial. In this study, we developed BRAFi-resistant melanoma cell lines and found that metastasis-related epithelial to mesenchymal ...[more]

PMID: 25243790

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Project description:Primary and posttreatment resistance to BRAFV600 mutation-targeting inhibitors leads to disease relapse in a majority of melanoma patients. In many instances, this resistance is promoted by upregulation of mitochondrial oxidative phosphorylation (OxPhos) in melanoma cells. We recently showed that a novel electron transport chain (ETC) complex I inhibitor, IACS-010759 (IACS), abolished OxPhos and significantly inhibited tumor growth of high-OxPhos, BRAF inhibitor (BRAFi)-resistant human melanomas. However, the inhibition was not uniform across different high OxPhos melanomas, and combination with BRAFi did not improve efficacy. We performed a high-throughput unbiased combinatorial drug screen of clinically relevant small molecules to identify the most potent combination agent with IACS for inhibiting the growth of high-OxPhos, BRAFi-resistant melanomas. We performed bioenergetics and carbon-13 metabolite tracing to delineate the metabolic basis of sensitization of melanomas to the combination treatment. We performed xenograft tumor growth studies and Reverse-Phase Protein Array (RPPA)-based functional proteomics analysis of tumors from mice fed with regular or high-fat diet to evaluate in vivo molecular basis of sensitization to the combination treatment. A combinatorial drug screen and subsequent validation studies identified Atorvastatin (STN), a hydroxymethylglutaryl-coenzyme A reductase inhibitor (HMGCRi), as the most potent treatment combination with IACS to inhibit in vitro cell growth and induce tumor regression or stasis of some BRAFi-resistant melanomas. Bioenergetics analysis revealed a dependence on fatty acid metabolism in melanomas that responded to the combination treatment. RPPA analysis and carbon-13 tracing analysis in these melanoma cells showed that IACS treatment decreased metabolic fuel utilization for fatty acid metabolism, but increased substrate availability for activation of the mevalonate pathway by HMGCR, creating a dependence on this pathway. Functional proteomic analysis showed that IACS treatment inhibited MAPK but activated AKT pathway. Combination treatment with STN counteracted AKT activation. STN and other clinically approved HMGCRi could be promising combinatorial agents for improving the efficacy of ETC inhibitors like IACS in BRAFi-resistant melanomas.

Dataset Information

Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas.

Publications

Epigenetic changes of EGFR have an important role in BRAF inhibitor-resistant cutaneous melanomas.

Similar Datasets

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