ArticleInternational journal of molecular sciences2019
Kinase-Inactivated EGFR Is Required for the Survival of Wild-Type EGFR-Expressing Cancer Cells Treated with Tyrosine Kinase Inhibitors.
Article in International journal of molecular sciences, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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Who cites it
23 citing papers in PubMed, 32 citations in OpenAlex.
- A Novel Aerogel Delivery System Reduces Drug Resistance for Non-Small Cell Lung Cancer Combination Therapy.Cancer medicine · 2026Article
- Deprivation of EGFR signal causes senolysis in PDAC with CDK4/6 inhibition.Cell death and differentiation · 2026Article
- Exploiting tumor lineage features for precision cancer therapy.Trends in cancer · 2026Review
- Bridging metabolic reprogramming and targeted therapy: the critical role of S-palmitoylation in cancer.Frontiers in cell and developmental biology · 2026Review
- zDHHC-Mediated S-Palmitoylation in Skin Health and Its Targeting as a Treatment Perspective.International journal of molecular sciences · 2025Review
- Palmitoylation in cancer: decoding its roles in signal transduction, tumor immunity, and emerging therapeutic opportunities.Frontiers in immunology · 2025Review
- EGFR-directed antibodies promote HER2 ADC internalization and efficacy.Cell reports. Medicine · 2024Article
- Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway.Respiratory research · 2024Article
- Targeting Epidermal Growth Factor Receptor for Cancer Treatment: Abolishing Both Kinase-Dependent and Kinase-Independent Functions of the Receptor.Pharmacological reviews · 2023Review
- Palmitoyl acyltransferase ZDHHC7 inhibits androgen receptor and suppresses prostate cancer.Oncogene · 2023Article
- Article
- Protein palmitoylation in cancer: molecular functions and therapeutic potential.Molecular oncology · 2023Review
- A multifunctional nanotheranostic agent potentiates erlotinib to EGFR wild-type non-small cell lung cancer.Bioactive materials · 2022Article
- Engaging innate immunity for targeting the epidermal growth factor receptor: Therapeutic options leveraging innate immunity versus adaptive immunity versus inhibition of signaling.Frontiers in oncology · 2022Review
- Tyrosine kinase-independent actions of DDR2 in tumor cells and cancer-associated fibroblasts influence tumor invasion, migration and metastasis.Journal of cell science · 2021Article
- Anticancer Activity and Mechanisms of Action of New Chimeric EGFR/HDAC-Inhibitors.International journal of molecular sciences · 2021Article
- MIG-6 is essential for promoting glucose metabolic reprogramming and tumor growth in triple-negative breast cancer.EMBO reports · 2021Article
- Treatment of Brain Metastases of Non-Small Cell Lung Carcinoma.International journal of molecular sciences · 2021Review
- Identification of Key Genes With Differential Correlations in Lung Adenocarcinoma.Frontiers in cell and developmental biology · 2021Article
- Phase I Trial to Evaluate the Tolerance, Pharmacokinetics and Efficacy of the Broad-Spectrum ErbB Family Inhibitor Larotinib Mesylate in Patients With Advanced Solid Tumors.Frontiers in pharmacology · 2021Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Inhibiting the tyrosine kinase activity of epidermal growth factor receptor (EGFR) using small molecule tyrosine kinase inhibitors (TKIs) is often ineffective in treating cancers harboring wild-type EGFR (wt-EGFR). TKIs are known to cause dimerization of EGFR without altering its expression level. Given the fact that EGFR possesses kinase-independent pro-survival function, the role of TKI-inactivated EGFR in cancer cell survival needs to be addressed. In this study, using wt-EGFR-expressing cancer cells A549 (lung), DU145 (prostate), PC3 (prostate), and MDA-MB-231 (breast), we characterized the TKI-induced dimerization status of EGFR and determined the dependency of cells on kinase-inactivated EGFR for survival. We report that TKI-induced EGFR dimerization is dependent on palmitoylation and independent of its kinase activity, and that mutations of the cysteine residues known to be critical for EGFR's palmitoylation abolished TKI-induced EGFR dimerization. Furthermore, TKI-induced EGFR dimerization is persistent in TKI-resistant cells, and inhibition of palmitoylation by 2-bromopalmitate, or targeted reduction of the kinase-inactivated EGFR by siRNA or by an EGFR-downregulating peptide, are lethal to TKI-resistant cancer cells. This study suggests that kinase-inactivated EGFR remains to be a viable therapeutic target for wt-EGFR cancers and that inhibiting palmitoylation or downregulating EGFR may overcome TKI resistance.
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