ArticleOncogene2018
ERK-dependent IL-6 autocrine signaling mediates adaptive resistance to pan-PI3K inhibitor BKM120 in head and neck squamous cell carcinoma.
Article in Oncogene, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 35 citations in OpenAlex.
- JAK-STAT signaling pathway in cancer: from molecular mechanisms to clinical intervention.Molecular cancer · 2026Review
- Mitochondrial fission enhances IL-6-induced metastatic potential in ovarian cancer via ERK1/2 activation.Cancer science · 2024Article
- Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers.Biomedicines · 2023Article
- Targeted therapy for head and neck cancer: signaling pathways and clinical studies.Signal transduction and targeted therapy · 2023Review
- Functional proteomics of patient derived head and neck squamous cell carcinoma cells reveal novel applications of trametinib.Cancer biology & therapy · 2022Article
- Resistance to PI3Kδ inhibitors in marginal zone lymphoma can be reverted by targeting the IL-6/PDGFRA axis.Haematologica · 2022Article
- Hydroxychloroquine synergizes with the PI3K inhibitor BKM120 to exhibit antitumor efficacy independent of autophagy.Journal of experimental & clinical cancer research : CR · 2021Article
- Mitochondrial genome and its regulator TFAM modulates head and neck tumourigenesis through intracellular metabolic reprogramming and activation of oncogenic effectors.Cell death & disease · 2021Article
- The functional GRHL3-filaggrin axis maintains a tumor differentiation potential and influences drug sensitivity.Molecular therapy : the journal of the American Society of Gene Therapy · 2021Article
- Embryonic protein NODAL regulates the breast tumor microenvironment by reprogramming cancer-derived secretomes.Neoplasia (New York, N.Y.) · 2021Article
- Research update on the anticancer effects of buparlisib.Oncology letters · 2021Review
- Association Between Interleukin-6 and Head and Neck Squamous Cell Carcinoma: A Systematic Review.Clinical and experimental otorhinolaryngology · 2021Review
- Human cytomegalovirus protein UL136 activates the IL-6/STAT3 signal through MiR-138 and MiR-34c in gastric cancer cells.International journal of clinical oncology · 2020Article
- TAM family receptors in conjunction with MAPK signalling are involved in acquired resistance to PI3Kα inhibition in head and neck squamous cell carcinoma.Journal of experimental & clinical cancer research : CR · 2020Article
- Multilevel defects in the hematopoietic niche in essential thrombocythemia.Haematologica · 2020Article
- Endothelial Cells Promote Docetaxel Resistance of Prostate Cancer Cells by Inducing ERG Expression and Activating Akt/mTOR Signaling Pathway.Frontiers in oncology · 2020Article
- ERK is a Pivotal Player of Chemo-Immune-Resistance in Cancer.International journal of molecular sciences · 2019Review
- Inhibition of cisplatin-resistant head and neck squamous cell carcinoma by combination of Afatinib with PD0325901, a MEK inhibitor.American journal of cancer research · 2019Article
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
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.
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