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Blocking Mitochondrial Respiration in Melanoma Cells Prevents Development of Drug Resistance

By BiotechDaily International staff writers
Posted on 24 Jun 2013
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Inhibition of oxidative phosphorylation (mitochondrial respiration) in a subpopulation of slow-growing, drug-resistant melanoma cells may augment traditional chemotherapy for treatment of this cancer, which is initially effective but eventually fails due to the development of drug resistance.

Despite success with BRAF-V600E inhibitors, therapeutic responses in patients with metastatic melanoma are short-lived because of the acquisition of drug resistance. The BRAF (v-Raf murine sarcoma viral oncogene homolog B1) gene encodes the protein serine/threonine-protein kinase B-Raf. Mutations in BRAF can cause disease by either congenital or acquired mutations. About half of melanomas express the BRAF-V600E mutation (at amino acid position number 600 on the B-Raf protein, the normal valine is replaced by glutamic acid). Inhibitors of B-Raf such as vemurafenib have been approved for the treatment of metastatic melanoma since August 2011.

Treatment of metastatic melanomas with various drugs, including cisplatin and vemurafenib, uniformly leads to enrichment of a population of slow-cycling, long-term tumor-maintaining melanoma cells that express the demethylase enzyme JARID1B (lysine-specific demethylase 5B, also known as histone demethylase). The slow-growing JARID1B cells represent only 1% to 5% of the cells in a tumor, yet readily convert into fast-growing metastatic melanoma cells following drug treatment and elimination of the bulk of the tumor.

Investigators at The Wistar Institute (Philadelphia, PA, USA) used advanced analysis techniques to perform proteome-profiling on melanoma JARID1B cells. Results published in the June 10, 2013, issue of the journal Cancer Cell revealed an upregulation in enzymes of mitochondrial oxidative-ATP-synthesis (oxidative phosphorylation) in this subpopulation. Despite the apparent slow replication of these cells, they were continually synthesizing glucose, which was then used to produce chemical energy. Inhibition of mitochondrial respiration with the diabetes drug phenformin blocked the conversion of the JARID1B subpopulation into the fast-growing form of melanoma cells and sensitized the melanoma to therapy, independent of genotype.

“We have found that the individual cells within melanoma tumors are not all identical, and tumors contain a subpopulation of cells that are inherently drug resistant, which accounts for the fact that advanced melanoma tumors return no matter how much the tumor is depleted,” said senior author Dr. Meenhard Herlyn, professor of molecular and cellular oncogenesis at The Wistar Institute. “We found that these slow-growing, drug-resistant cells are marked by a high rate of metabolism, which makes them susceptible to diabetes therapeutics. Our findings suggest a simple strategy to kill metastatic melanoma—regardless of cell type within the tumor—by combining anticancer drugs with a diabetes drug. The diabetes drug puts the brakes on the cells that would otherwise repopulate the tumor, thus allowing the anticancer drug to be more effective.”

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The Wistar Institute


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