The discovery of activating BRAF V600E mutations in 50% of all melanoma patients 
and the development of small molecule BRAF inhibitors looks set to revolutionize 
the therapy of disseminated melanoma. However, in the recent clinical trial of 
the BRAF inhibitor, vemurafenib (PLX4032), a significant percentage of BRAF 
V600E mutant melanoma patients did not meet the RECIST criteria for a response. 
Recent work from our lab identified loss of the tumor suppressor phosphatase and 
tensin homolog (PTEN) as being a possible mediator of intrinsic BRAF inhibitor 
resistance. In this commentary, we describe the development of a novel mass 
spectrometry based proteomic screen of Bcl-2 family proteins that was used to 
delineate the PTEN-dependent differences in apoptosis signaling observed when 
BRAF was inhibited. We further discuss how use of these sensitive quantitative 
proteomic methods gives unique insights into the signaling of cancer cells that 
are not captured through routine biochemical techniques and how this may lead to 
the development of combination therapy strategies for overcoming intrinsic BRAF 
inhibitor resistance.