RRC ID 67145
Author Yun MR, Choi HM, Kang HN, Lee Y, Joo HS, Kim DH, Kim HR, Hong MH, Yoon SO, Cho BC.
Title ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma.
Journal Oncogene
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.
Volume 37(3)
Pages 377-388
Published 2018-1-18
DOI 10.1038/onc.2017.339
PII onc2017339
PMID 28945228
MeSH Aminopyridines / pharmacology* Aminopyridines / therapeutic use Animals Antibodies, Monoclonal, Humanized / pharmacology Antibodies, Monoclonal, Humanized / therapeutic use Antineoplastic Combined Chemotherapy Protocols / pharmacology* Antineoplastic Combined Chemotherapy Protocols / therapeutic use Autocrine Communication / drug effects Carcinoma, Squamous Cell / drug therapy* Carcinoma, Squamous Cell / pathology Cell Line, Tumor Cell Proliferation / drug effects Drug Resistance, Neoplasm* Extracellular Signal-Regulated MAP Kinases / metabolism Female Head and Neck Neoplasms / drug therapy* Head and Neck Neoplasms / pathology Humans Interleukin-6 / genetics Interleukin-6 / metabolism* MAP Kinase Signaling System / drug effects Mice Mice, Inbred NOD Morpholines / pharmacology* Morpholines / therapeutic use Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors* Protein Kinase Inhibitors / pharmacology* Protein Kinase Inhibitors / therapeutic use Pyridones / pharmacology Pyridones / therapeutic use Pyrimidinones / pharmacology Pyrimidinones / therapeutic use RNA, Small Interfering / metabolism Receptors, Interleukin-6 / antagonists & inhibitors Receptors, Interleukin-6 / metabolism STAT3 Transcription Factor / metabolism Squamous Cell Carcinoma of Head and Neck Xenograft Model Antitumor Assays
IF 7.971
Human and Animal Cells HSC-2(RCB1945)