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Oncotarget. 2016 Apr 5;7(14):17665-80. doi: 10.18632/oncotarget.6882.

BRAF inhibitor resistance enhances vulnerability to arginine deprivation in melanoma.

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Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida, USA.
Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, Florida, USA.
Division of Hematology and Oncology, Miami Veterans Affairs Healthcare System, Miami, Florida, USA.
Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Tao-Yuan, Taiwan.
Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei, Taiwan.
Dauer Electron Microscopy Laboratory, Department of Biology, University of Miami, Miami, FL, USA.
Department of Surgery, University of Miami Miller School of Medicine, Miami, Florida, USA.
Department of Molecular Pathology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Department of Laboratory Medicine, Miami Veterans Affairs Healthcare System, Miami, Florida, USA.


BRAF inhibitor (BRAFi) has been used for treatment of melanomas harboring V600E mutation. Despite a high initial response rate, resistance to BRAFi is inevitable. Here, we demonstrate that BRAFi-resistant (BR) melanomas are susceptible to arginine deprivation due to inability to initiate re-expression of argininosuccinate synthetase (ASS1, a key enzyme for arginine synthesis) as well as ineffective autophagy. Autophagy and ASS1 re-expression are known to protect melanoma cells from cell death upon arginine deprivation. When melanoma cells become BR cells by long-term in vitro incubation with BRAFi, c-Myc-mediated ASS1 re-expression and the levels of autophagy-associated proteins (AMPK-α1 and Atg5) are attenuated. Furthermore, our study uncovers that downregulation of deubiquitinase USP28 which results in more active c-Myc degradation via ubiquitin-proteasome machinery is the primary mechanism for inability to re-express ASS1 upon arginine deprivation in BR cells. Overexpression of USP28 in BR cells enhances c-Myc expression and hence increases ASS1 transcription upon arginine deprivation, and consequently leads to cell survival. On the other hand, overexpression of Atg5 or AMPK-α1 in BR cells can redirect arginine deprivation-induced apoptosis toward autophagy. The xenograft models also confirm that BR tumors possess lower expression of ASS1 and are hypersensitive to arginine deprivation. These biochemical changes in BRAFi resistance which make them vulnerable to arginine deprivation can be exploited for the future treatment of BR melanoma patients.


ASS1 re-expression; BRAF inhibitor resistance; arginine deprivation; autophagy; ubiquitin-proteasome machinery

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