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Oncogene Study Identifies Drug Resistance in BRAF/PTEN-Null Melanoma

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Using mass-spectrometry—based phosphoproteomics, researchers at the Moffit Cancer Center have identified a mechanism by which BRAF/PTEN-null melanoma cells develop resistance to BRAF inhibitors.

Researchers at the Moffit Cancer Center have identified a mechanism by which BRAF/PTEN-null melanoma cells develop resistance to BRAF inhibitors. Using mass-spectrometry—based phosphoproteomics, the researchers found that treating these mutant-bearing melanoma cells with a BRAF inhibitor was associated with marked changes in fibronectin-based adhesion signaling that were PTEN dependent. These results are a step in the direction of developing combination therapies to prevent resistance and relapse in melanoma patients. Nearly 50% of melanoma patients harbor BRAF mutations and many of these patients relapse on these treatments. Identifying the mechanism of resistance is very important as a prevention strategy.

In their report in Oncogene, the authors present data showing an upregulation of the adhesion molecule fibronectin in a mouse melanoma model, with exposure to a BRAF inhibitor. The authors also conducted a phosphoproteomic analysis of patient tumor samples and identified a similar trend: those treated with a BRAF inhibitor had increased fibronectin expression and signaling, which was PTEN-dependent. Further, induction of fibronectin was associated with reduced overall survival due to a reduced response to the BRAF inhibitor.

The work has significant clinical implications with respect to developing novel combination strategies in melanoma.

Read more at ScienceDaily.

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