Abstract
Hyperactivation of phosphatidylinositol 3-kinase (PI3K) pathway occurs frequently in head and neck squamous cell carcinoma (HNSCC). However, clinical outcomes of targeting the PI3K pathway have been underwhelming. In present study, we investigated the resistant mechanisms and potential combination therapeutic strategy to overcome adaptive resistance to PI3K inhibitor in HNSCC. Treatment of NVP-BKM120, a pan-PI3K inhibitor, led to upregulation of interleukin-6 (IL-6) and subsequent activation of either extracellular signal-regulated kinase (ERK) or signal transducers and activators of transcription 3 (STAT3), causing modest antitumor effects on the growth of HNSCC cells. Blockade of autocrine IL-6 signaling with siRNA or neutralizing antibody for IL-6 receptor (IL-6R) completely abolished NVP-BKM120-induced activation of ERK and STAT3 as well as expression of c-Myc oncogene, which resulted in enhanced sensitivity to NVP-BKM120. Moreover, when compared with a pharmacologic inhibitor or silencing of STAT3, trametinib, a MEK inhibitor, in combination with NVP-BKM120 yielded more potent anti-proliferative effects by inhibiting S phase transition, arresting cells at G0/G1 phase, and downregulating IL-6 and c-Myc expression. Furthermore, as compared with either agent alone, combination of NVP-BKM120 with trametinib or tocilizumab, a humanized anti-IL-6R antibody, significantly suppressed tumor growth in NVP-BKM120-resistant patient-derived tumor xenograft (PDTX) models, which was also confirmed in PDTX-derived cell lines. Collectively, these results suggested that IL-6/ERK signaling is closely involved in adaptive resistance of NVP-BKM120 in HNSCC cells, providing a rationale for a novel combination therapy to overcome resistance to PI3K inhibitors.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aminopyridines / pharmacology*
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Aminopyridines / therapeutic use
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology
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Antibodies, Monoclonal, Humanized / therapeutic use
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Autocrine Communication / drug effects
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Carcinoma, Squamous Cell / drug therapy*
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Carcinoma, Squamous Cell / pathology
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Drug Resistance, Neoplasm*
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Extracellular Signal-Regulated MAP Kinases / metabolism
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Female
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Head and Neck Neoplasms / drug therapy*
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Head and Neck Neoplasms / pathology
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Humans
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Interleukin-6 / genetics
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Interleukin-6 / metabolism*
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MAP Kinase Signaling System / drug effects
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Mice
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Mice, Inbred NOD
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Morpholines / pharmacology*
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Morpholines / therapeutic use
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors*
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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Pyridones / pharmacology
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Pyridones / therapeutic use
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Pyrimidinones / pharmacology
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Pyrimidinones / therapeutic use
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RNA, Small Interfering / metabolism
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Receptors, Interleukin-6 / antagonists & inhibitors
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Receptors, Interleukin-6 / metabolism
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STAT3 Transcription Factor / metabolism
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Squamous Cell Carcinoma of Head and Neck
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Xenograft Model Antitumor Assays
Substances
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Aminopyridines
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Antibodies, Monoclonal, Humanized
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IL6 protein, human
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IL6R protein, human
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Interleukin-6
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Morpholines
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NVP-BKM120
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Phosphoinositide-3 Kinase Inhibitors
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Protein Kinase Inhibitors
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Pyridones
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Pyrimidinones
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RNA, Small Interfering
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Receptors, Interleukin-6
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STAT3 Transcription Factor
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STAT3 protein, human
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trametinib
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Extracellular Signal-Regulated MAP Kinases
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tocilizumab