Drug-resistant melanomas require combination therapy

Thursday December 23, 2010

As highlighted at the November 2010 Sydney Melanoma Congress, recent trials have shown that some melanomas containing a mutation in the BRAF gene have been successfully treated with BRAF-specific inhibitors. It was reported, for example, that PLX4032 improved progression-free survival of approximately two months and median overall survival of six to nine months. Yet in some cases tumours returned and resumed growing following treatment.

As outlined in a press release from The Wistar Institute Melanoma Research Center, authors of a recently published study offer an explanation as to why a melanoma “learns to signal around the blocked gene by adjusting its molecular wiring”. They also show how to “overcome resistance by simultaneously targeting multiple signalling pathways”.

“The researchers see this as further evidence that some cancers must be treated with multiple targeted drugs at the outset of treatment.” Their findings are published in the December 14 issue of the journal Cancer Cell.

Article highlights:
• Chronic BRAF inhibition in BRAFV600E melanoma cells leads to drug resistance
• BRAF inhibitor resistant cells switch among the three RAF isoforms to activate MAPK
• IGF1R/PI3K signalling promotes survival of BRAF-inhibitor resistant cells
• Coinhibition of MEK and IGF1R/PI3K leads to cytotoxicity in resistant melanoma cells

Press release source: http://www.wistar.org/news_info/pressreleases/pr_12.13.10.htm

Published article: Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K. Cancer Cell, Volume 18, Issue 6, 683-695, 14 December 2010
http://www.cell.com/cancer-cell/abstract/S1535-6108%2810%2900484-8