New hope in the fight against melanoma

December 14th, 2010 - 6:39 pm ICT by ANI  

Washington, Dec 14 (ANI): Scientists have offered new hope in the fight against melanoma, most aggressive form of skin cancer.

This past summer saw a revolution in melanoma therapy. Patients whose melanoma lesions contain a mutation in the BRAF gene were successfully treated with a BRAF-specific inhibitor, PLX4032.

Reports of the drug trial described shrinking tumors and improved health. Yet seven months after therapy began the tumors returned and resumed growing.

Now, scientists at The Wistar Institute explain why: the tumor learns to signal around the blocked gene by adjusting its molecular wiring. They also show how to overcome resistance by simultaneously targeting multiple signaling pathways.

“The evidence suggests that targeting mutant BRAF can kill cancer cells, but it is not enough by itself to finish off melanoma,” said Meenhard Herlyn, director of The Wistar Institute Melanoma Research Center.

“The good news is that drugs are being developed to work in combination with BRAF inhibitors, which our data clearly shows is our best option if we intend to beat advanced melanoma,” Herlyn said.

To study how melanoma responds to BRAF inhibitors, the Herlyn lab took melanoma cells with the BRAF mutation and tested them against a variety of anti-mutant BRAF drugs.

When exposed to the drugs, the cells died off dramatically only to grow back again. In fact, cells that became resistant to one type of BRAF drug became resistant to all of them, which suggests that the cells were biochemically “rewired” in such a way that they no longer needed BRAF to form tumors.

First, they found that resistant cells used a protein similar to BRAF to carry the signal down the chain. Second, they found these cells received an additional boost from the IGF-1 receptor, a protein that sits on the surface of cells and sends signals that prevent cells from being killed.

The resistant cells re-route the signal around BRAF by switching to an alternate protein (CRAF or ARAF), which promotes tumor cell growth, while IGF-1R signaling promotes survival of the resistant cells.

Their findings are published in the December 14 issue of the journal Cancer Cell. (ANI)

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