Abstract
Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment.
©2015 American Association for Cancer Research.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / pharmacology
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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Benzamides / pharmacology
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Blotting, Western
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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 Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Cisplatin / pharmacology*
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Diphenylamine / analogs & derivatives
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Diphenylamine / pharmacology
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics
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Gene Expression Profiling / methods
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Gene Expression Regulation, Neoplastic
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Humans
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Lung Neoplasms / drug therapy*
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / genetics
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mice, SCID
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / genetics
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Mitogen-Activated Protein Kinase Kinases / metabolism*
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Proteomics / methods
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / metabolism
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RNA Interference
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Reverse Transcriptase Polymerase Chain Reaction
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Son of Sevenless Proteins / genetics
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Son of Sevenless Proteins / metabolism*
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Tumor Burden / drug effects
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Tumor Burden / genetics
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Xenograft Model Antitumor Assays
Substances
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Antineoplastic Agents
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Apoptosis Regulatory Proteins
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BCL2L11 protein, human
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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Benzamides
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Membrane Proteins
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Proto-Oncogene Proteins
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Son of Sevenless Proteins
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mirdametinib
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Diphenylamine
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Mitogen-Activated Protein Kinase Kinases
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Cisplatin