BH3-only protein silencing contributes to acquired resistance to PLX4720 in human melanoma.

Abstract

B-RAF is mutated to a constitutively active form in 8% of human cancers including 50% of melanomas. In clinical trials, the RAF inhibitor, PLX4032 (vemurafenib), caused partial or complete responses in 48-81% of mutant B-RAF harboring melanoma patients. However, the average duration of response was 6-7 months before tumor regrowth, indicating the acquisition of resistance to PLX4032. To understand the mechanisms of resistance, we developed mutant B-RAF melanoma cells that displayed resistance to RAF inhibition through continuous culture with PLX4720 (the tool compound for PLX4032). Resistance was associated with a partial reactivation of extracellular signal-regulated kinase 1/2 (ERK1/2) signaling, recovery of G1/S cell-cycle events, and suppression of the pro-apoptotic B-cell leukemia/lymphoma 2 (Bcl-2) homology domain 3 (BH3)-only proteins, Bcl-2-interacting mediator of cell death-extra large (Bim-EL) and Bcl-2 modifying factor (Bmf). Preventing ERK1/2 reactivation with MEK (mitogen-activated protein/extracellular signal-regulated kinase kinase) inhibitors blocked G1-S cell-cycle progression but failed to induce apoptosis or upregulate Bim-EL and Bmf. Treatment with the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid, led to de-repression of Bim-EL and enhanced cell death in the presence of PLX4720 or AZD6244 in resistant cells. These data indicate that acquired resistance to PLX4032/4720 likely involves ERK1/2 pathway reactivation as well as ERK1/2-independent silencing of BH3-only proteins. Furthermore, combined treatment of HDAC inhibitors and MEK inhibitors may contribute to overcoming PLX4032 resistance.

• Authors: Y Shao, A E Aplin
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 19 Issue 12 Pg. 2029-39 (Dec 2012) ISSN: 1476-5403 [Electronic] England
• PMID: 22858545 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• BCL2L11 protein, human
• BMF protein, human
• Bcl-2-Like Protein 11
• Hydroxamic Acids
• Indoles
• Membrane Proteins
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• Sulfonamides
• Vemurafenib
• Vorinostat
• Proto-Oncogene Proteins B-raf
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3
• Histone Deacetylases

Topics

• Adaptor Proteins, Signal Transducing (genetics, metabolism)
• Apoptosis (drug effects)
• Apoptosis Regulatory Proteins (genetics, metabolism)
• Bcl-2-Like Protein 11
• Cell Line, Tumor
• Drug Resistance, Neoplasm (drug effects)
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Histone Deacetylases (chemistry, metabolism)
• Humans
• Hydroxamic Acids (pharmacology)
• Indoles (toxicity)
• Melanoma (metabolism, pathology)
• Membrane Proteins (genetics, metabolism)
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Proto-Oncogene Proteins (genetics, metabolism)
• Proto-Oncogene Proteins B-raf (metabolism)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• S Phase Cell Cycle Checkpoints (drug effects)
• Sulfonamides (toxicity)
• Up-Regulation
• Vemurafenib
• Vorinostat