Abstract
Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3-mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with the combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Apoptosis / drug effects
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Biphenyl Compounds / administration & dosage
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Biphenyl Compounds / pharmacology*
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / genetics
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Carcinoma, Squamous Cell / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Drug Synergism
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F-Box Proteins / genetics
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F-Box Proteins / metabolism*
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F-Box-WD Repeat-Containing Protein 7
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Histone Deacetylase Inhibitors / administration & dosage
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Histone Deacetylase Inhibitors / pharmacology*
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Histone Deacetylases / genetics
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Histone Deacetylases / metabolism*
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Humans
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Hydroxamic Acids / administration & dosage
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Hydroxamic Acids / pharmacology
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Mice
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Mice, Nude
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Myeloid Cell Leukemia Sequence 1 Protein / genetics
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Myeloid Cell Leukemia Sequence 1 Protein / metabolism*
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Nitrophenols / administration & dosage
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Nitrophenols / pharmacology*
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Piperazines / administration & dosage
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Piperazines / pharmacology
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Proto-Oncogene Proteins c-bcl-2 / antagonists & inhibitors*
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology*
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Transfection
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / metabolism*
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Vorinostat
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Xenograft Model Antitumor Assays
Substances
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ABT-737
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Biphenyl Compounds
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Cell Cycle Proteins
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F-Box Proteins
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F-Box-WD Repeat-Containing Protein 7
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FBXW7 protein, human
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Histone Deacetylase Inhibitors
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Hydroxamic Acids
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MCL1 protein, human
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Myeloid Cell Leukemia Sequence 1 Protein
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Nitrophenols
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Piperazines
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Proto-Oncogene Proteins c-bcl-2
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Sulfonamides
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Vorinostat
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Ubiquitin-Protein Ligases
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Histone Deacetylases