ArticleCancer research2009
Sustained Src inhibition results in signal transducer and activator of transcription 3 (STAT3) activation and cancer cell survival via altered Janus-activated kinase-STAT3 binding.
Article in Cancer research, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
70 citing papers in PubMed, 130 citations in OpenAlex.
- Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.JCI insight · 2017Trial
- Trial
- Phase II study of saracatinib (AZD0530) for patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC).Anticancer research · 2011Trial
- Phase II study of dasatinib in patients with advanced non-small-cell lung cancer.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2010Trial
- Article
- Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia.Signal transduction and targeted therapy · 2025Article
- Pathogenic Pathways and Therapeutic Strategies in Autosomal Dominant Polycystic Kidney Disease (ADPKD).Journal of cellular signaling · 2025Article
- Androgen receptor activation promotes tumor progression in canine and human triple negative breast cancer cell lines.Frontiers in veterinary science · 2025Article
- Adverse drug events associated with tiotropium: a real-world pharmacovigilance study of FDA adverse event reporting system database.Journal of pharmacy & pharmaceutical sciences : a publication of the Canadian Society for Pharmaceutical Sciences, Societe canadienne des sciences pharmaceutiques · 2025Article
- JAK-STAT Signaling in Autoimmunity and Cancer.ImmunoTargets and therapy · 2025Review
- STAT3 Regulates the Redox Profile in MDA-MB-231 Breast Cancer Cells.Cell biochemistry and biophysics · 2024Article
- Mometasone Furoate Inhibits the Progression of Head and Neck Squamous Cell Carcinoma via Regulating Protein Tyrosine Phosphatase Non-Receptor Type 11.Biomedicines · 2023Article
- Identification of Gene-Tyrosine Kinase 2 (TYK2) in Head and Neck Squamous Cell Carcinoma Patients-An Integrated Bioinformatics Approach.Disease markers · 2022Article
- Review
- Review
- Gallic acid suppresses colon cancer proliferation by inhibiting SRC and EGFR phosphorylation.Experimental and therapeutic medicine · 2021Article
- Candesartan ameliorates vascular smooth muscle cell proliferation via regulating miR-301b/STAT3 axis.Human cell · 2020Article
- Targeting STAT-3 signaling pathway in cancer for development of novel drugs: Advancements and challenges.Genetics and molecular biology · 2020Article
- Characterization of epidermal growth factor receptor (EGFR) P848L, an unusual EGFR variant present in lung cancer patients, in a murine Ba/F3 model.FEBS open bio · 2019Article
- TYK2 promotes malignant peripheral nerve sheath tumor progression through inhibition of cell death.Cancer medicine · 2019Article
10 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Locoregional and distant recurrence remains common and usually fatal for patients with advanced head and neck squamous cell carcinoma (HNSCC). One promising molecular target in HNSCC is the Src family kinases (SFK). SFKs can affect cellular proliferation and survival by activating the signal transducer and activator of transcription (STAT) family of transcription factors, especially STAT3. Surprisingly, sustained SFK inhibition resulted in only transient inhibition of STAT3. We investigated the mechanism underlying STAT3 activation and its biological importance. Specific c-Src knockdown with small interfering RNA (siRNA) resulted in STAT3 activation showing specificity, which was inhibited by Janus-activated kinase (JAK; TYK2 and JAK2) depletion with siRNA. Sustained SFK inhibition also resulted in recovered JAK-STAT3 binding and JAK kinase activity after an initial reduction, although JAK phosphorylation paradoxically decreased. To determine the biological significance of STAT3 activation, we combined specific STAT3 depletion with a pharmacologic SFK inhibitor and observed increased cell cycle arrest and apoptosis. Likewise, the addition of STAT3- or JAK-specific siRNA to c-Src-depleted cells enhanced cytotoxicity relative to cells incubated with c-Src siRNA alone. These results show that reactivation of STAT3 after sustained, specific c-Src inhibition is mediated through altered JAK-STAT3 binding and JAK kinase activity and that this compensatory pathway allows for cancer cell survival and proliferation despite durable c-Src inhibition. To our knowledge, this novel feedback pathway has never been described previously. Given that pharmacologic SFK inhibitors are currently being evaluated in clinical trials, these results have potential clinical implications for cancer therapy.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.