Abstract
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.
Highlights
Melanoma is the deadliest form of skin cancer
In the phase I clinical trial, vemurafenib led to significant levels of tumor shrinkage in 80% of patients whose melanomas harbored the BRAF V600E mutation [20]
Using proteomics to understand the mechanisms of intrinsic BRAF inhibitor resistance Approximately 20% of BRAF V600E mutant melanoma patients on the phase I trial of vemurafenib appeared to be intrinsically resistant and did not meet the RECIST criteria for a response [20]
Summary
Melanoma is the deadliest form of skin cancer. It arises from the malignant transformation of melanocytes and has long been notorious for its resistance to chemotherapy, radiotherapy and immunotherapy. In the phase I clinical trial, vemurafenib led to significant levels of tumor shrinkage in 80% of patients whose melanomas harbored the BRAF V600E mutation [20].
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