ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma

Autor: D. H. Kim, Min Hee Hong, Yw Lee, H. N. Kang, H. S. Joo, M. R. Yun, Byoung Chul Cho, H. M. Choi, Hye Ryun Kim, Sang-Oh Yoon
Rok vydání: 2016
Předmět:
0301 basic medicine
MAPK/ERK pathway
STAT3 Transcription Factor
Cancer Research
MAP Kinase Signaling System
Pyridones
Morpholines
Aminopyridines
Pyrimidinones
Biology
Antibodies
Monoclonal
Humanized
03 medical and health sciences
Mice
Phosphatidylinositol 3-Kinases
0302 clinical medicine
Mice
Inbred NOD
Cell Line
Tumor
Antineoplastic Combined Chemotherapy Protocols
Genetics
medicine
Animals
Humans
RNA
Small Interfering
Autocrine signalling
Extracellular Signal-Regulated MAP Kinases
Molecular Biology
Protein Kinase Inhibitors
PI3K/AKT/mTOR pathway
Cell Proliferation
Phosphoinositide-3 Kinase Inhibitors
Trametinib
Oncogene
Cell growth
Interleukin-6
Squamous Cell Carcinoma of Head and Neck
MEK inhibitor
medicine.disease
Head and neck squamous-cell carcinoma
Receptors
Interleukin-6
Xenograft Model Antitumor Assays
Autocrine Communication
030104 developmental biology
Drug Resistance
Neoplasm
Head and Neck Neoplasms
030220 oncology & carcinogenesis
Cancer research
Carcinoma
Squamous Cell
Female
Zdroj: Oncogene. 37(3)
ISSN: 1476-5594
Popis: 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.
Databáze: OpenAIRE
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