ArticleClinical cancer research : an official journal of the American Association for Cancer Research2013
c-Src activation mediates erlotinib resistance in head and neck cancer by stimulating c-Met.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 67 papers.
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Who cites it
67 citing papers in PubMed, 97 citations in OpenAlex.
- Phase 1 trial of dasatinib combined with afatinib for epidermal growth factor receptor- (EGFR-) mutated lung cancer with acquired tyrosine kinase inhibitor (TKI) resistance.British journal of cancer · 2019Trial
- Randomized, placebo-controlled window trial of EGFR, Src, or combined blockade in head and neck cancer.JCI insight · 2017Trial
- Erlotinib, erlotinib-sulindac versus placebo: a randomized, double-blind, placebo-controlled window trial in operable head and neck cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2014Trial
- Article
- Differential Efficacy of Bevacizumab and Erlotinib in Preclinical Models of Renal Medullary Carcinoma and Fumarate Hydratase-Deficient Renal Cell Carcinoma.Molecular cancer therapeutics · 2025Article
- Review
- The MET Oncogene Network of Interacting Cell Surface Proteins.International journal of molecular sciences · 2024Review
- Evaluation of a Novel MET-Targeting Camelid-Derived Antibody in Head and Neck Cancer.Molecular pharmaceutics · 2024Article
- Structural Basis for Long Residence Time c-Src Antagonist: Insights from Molecular Dynamics Simulations.International journal of molecular sciences · 2024Article
- EGFR amplification and EGFRvIII predict and participate in TAT-Cx43266-283 antitumor response in preclinical glioblastoma models.Neuro-oncology · 2024Article
- Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.Cell reports. Medicine · 2024Article
- Decoding the research landscape of drug resistance and therapeutic approaches in head and neck cancer: a bibliometric analysis from 2000 to 2023.Frontiers in pharmacology · 2024Article
- Role of c-Src in Carcinogenesis and Drug Resistance.Cancers · 2023Review
- Multi-kinase compensation rescues EGFR knockout in a cell line model of head and neck squamous cell carcinoma.Archives of oral biology · 2023Article
- c-Src inhibitor PP2 inhibits head and neck cancer progression through regulation of the epithelial-mesenchymal transition.Experimental biology and medicine (Maywood, N.J.) · 2023Article
- Emerging tyrosine kinase inhibitors for head and neck cancer.Expert opinion on emerging drugs · 2022Review
- Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma.Head & neck · 2022Article
- Molecular mechanism(s) of regulation(s) of c-MET/HGF signaling in head and neck cancer.Molecular cancer · 2022Review
- Study of hsa_circRNA_000121 and hsa_circRNA_004183 in papillary thyroid microcarcinoma.Open life sciences · 2022Article
- Overcoming resistance to EGFR monotherapy in HNSCC by identification and inhibition of individualized cancer processes.Theranostics · 2022Article
7 more citing papers are in PubMed but not listed here.
Corrections and comments
- Erratum issuedThomas, Sufi [added]
Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeStrategies to inhibit the EGF receptor (EGFR) using the tyrosine kinase inhibitor erlotinib have been associated with limited clinical efficacy in head and neck squamous cell carcinoma (HNSCC). Co-activation of alternative kinases may contribute to erlotinib resistance. EXPERIMENTAL
designWe generated HNSCC cells expressing dominant-active c-Src (DA-Src) to determine the contribution of c-Src activation to erlotinib response.
resultsExpression of DA-Src conferred resistance to erlotinib in vitro and in vivo compared with vector-transfected control cells. Phospho-Met was strongly upregulated by DA-Src, and DA-Src cells did not produce hepatocyte growth factor (HGF). Knockdown of c-Met enhanced sensitivity to erlotinib in DA-Src cells in vitro, as did combining a c-Met or c-Src inhibitor with erlotinib. Inhibiting EGFR resulted in minimal reduction of phospho-Met in DA-Src cells, whereas complete phospho-Met inhibition was achieved by inhibiting c-Src. A c-Met inhibitor significantly sensitized DA-Src tumors to erlotinib in vivo, resulting in reduced Ki67 labeling and increased apoptosis. In parental cells, knockdown of endogenous c-Src enhanced sensitivity to erlotinib, whereas treatment with HGF to directly induce phospho-Met resulted in erlotinib resistance. The level of endogenous phospho-c-Src in HNSCC cell lines was also significantly correlated with erlotinib resistance.
conclusionsLigand-independent activation of c-Met contributes specifically to erlotinib resistance, not cetuximab resistance, in HNSCC with activated c-Src, where c-Met activation is more dependent on c-Src than on EGFR, providing an alternate survival pathway. Addition of a c-Met or c-Src inhibitor to erlotinib may increase efficacy of EGFR inhibition in patients with activated c-Src.
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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.