Oncotarget

Research Perspectives:

Using quantitative proteomic analysis to understand genotype specific intrinsic drug resistance in melanoma

John M. Koomen and Keiran S. M. Smalley _

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Oncotarget. 2011; 2:329-335. https://doi.org/10.18632/oncotarget.263

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Abstract

John M. Koomen1,2 & Keiran S. M. Smalley1,3,4

1 Program in Molecular Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA

2 Program in Experimental Therapeutics, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA

3 Program in Cutaneous Oncology, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA

4 The Comprehensive Melanoma Research Center, The Moffitt Cancer Center & Research Institute, Tampa, FL, USA

Keywords: Oncogene, cancer, kinase, BRAF V600E, drug resistance, proteomics

Received: April 13, 2011; Accepted: April 14, 2011; Published: April 15, 2011;

Correspondence:

Keiran S. M. Smalley, e-mail:

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.


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