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Resistance to BRAF Inhibitors Is More Complicated Than Thought

Resistance to BRAF Inhibitors Is More Complicated Than Thought | Melanoma Dispatch | Scoop.it

Two new studies show that several different genetic mutations can make melanoma tumors resist drugs known as BRAF inhibitors, complicating treatment. These mutations are in genes that are part of the 'MAPK pathway.' The first study was on BRAF-inhibitor resistant melanomas from 45 people. In about half of the tumors, one of a set of three genes (MEK1, MEK2, MITF) was abnormal, and in three of the tumors more than one was abnormal.

The second study compared melanomas before and after resistance to combination treatment with both BRAF and MEK inhibitors. Tumors from three of the five people in the study developed genetic abnormalities that were not seen before treatment. On a positive note, when cells from resistant melanomas with both BRAF and MEK mutations were grown in the laboratory, they responded to a drug that inhibits a related protein called ERK.

The mutations in this study were all found in genes that code for proteins in the MAPK pathway, a particular group of proteins in a cell that work together to control cell multiplication that can lead to tumor growth. Knowing exactly which mutations a melanoma has will help doctors target it with the right combination of treatments.

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Cancer Discovery│Nov 21, 2013

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SMURF2 Inhibitors Increase Effectiveness of MEK Inhibitors

Treatments that target a protein called MEK could work better when combined with drugs that inhibit a protein called SMURF2, according to research in the British Journal of the National Cancer Institute. MEK is involved in cell division and can be activated by BRAF and NRAS mutations. However, melanomas often resist MEK inhibitors. The researchers found that MEK inhibitors made melanoma cells grown in the laboratory produce too much of a protein called SMURF2. This in turn led to overproduction of another protein called MITF, which protects melanomas against MEK inhibitors. When treated with both a MEK inhibitor called selumetinib and a SMURF2 inhibitor, tumor growth was suppressed by 98% in mice.

 

Primary source: http://jnci.oxfordjournals.org/content/105/1/33.abstract?sid=76bd523d-0853-4b55-abe1-b7781898c5a3

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ScienceDaily | Dec 19, 2012

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