Because melanomas can quickly resist BRAF inhibitor drugs alone or in combination with MEK inhibitors, researchers are testing a new combination treatment: the BRAF inhibitor vemurafenib and PX-866, which inhibits a cancer pathway called PI3K. In a phase I/II clinical trial of 19 people with melanomas that have BRAF mutations, the vemurafenib/PX-866 combination shrank tumors in 10 of them. These findings were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia. However, while results so far are encouraging, it will take larger trials to see if this new combo treatment really overcomes drug resistance in melanomas. This ongoing trial is still accepting new participants.
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.