Academic Journal
Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors.
| Τίτλος: | Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors. |
|---|---|
| Συγγραφείς: | Cuellar-Vite L; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio., Donaubauer EM; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio., Weber-Bonk KL; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Bobbitt JR; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio., Ingles NN; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.; Department of Pathology, School of Medicine, Case Western Reserve University, Cleveland, Ohio., Brzozowski TL; Department of Pharmacology, School of Medicine, Case Western Reserve University, Cleveland, Ohio.; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio., Abdul-Karim FW; Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio., Booth CN; Anatomic Pathology, Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio., Keri RA; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio.; Department of General Medical Sciences-Oncology, School of Medicine, Case Western Reserve University, Cleveland, Ohio. |
| Πηγή: | Molecular cancer research : MCR [Mol Cancer Res] 2025 May 02; Vol. 23 (5), pp. 391-404. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 101150042 Publication Model: Print Cited Medium: Internet ISSN: 1557-3125 (Electronic) Linking ISSN: 15417786 NLM ISO Abbreviation: Mol Cancer Res Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Philadelphia, PA : American Association for Cancer Research, c2002- |
| Ιατρικοί όροι (MeSH): | Protein Kinase Inhibitors*/pharmacology , Triple Negative Breast Neoplasms*/drug therapy , Triple Negative Breast Neoplasms*/genetics , Triple Negative Breast Neoplasms*/pathology , Triple Negative Breast Neoplasms*/metabolism , Proto-Oncogene Proteins c-yes*/genetics , Proto-Oncogene Proteins c-yes*/metabolism , Carcinoma, Non-Small-Cell Lung*/drug therapy , Carcinoma, Non-Small-Cell Lung*/genetics , Carcinoma, Non-Small-Cell Lung*/pathology , Lung Neoplasms*/drug therapy , Lung Neoplasms*/genetics , Lung Neoplasms*/pathology, ErbB Receptors/genetics ; ErbB Receptors/antagonists & inhibitors ; ErbB Receptors/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Cell Proliferation/drug effects ; Humans ; Animals ; Mice ; Female ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Mutation |
| Περίληψη: | EGFR is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors (EGFRi) is limited to cancers that harbor sensitizing mutations in the EGFR gene because of dose-limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wild-type (WT) or mutant EGFR. We found that YES1 is highly expressed in triple-negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer cells, including those that harbor the EGFR gatekeeper mutation T790M. The novel ability of YES1 to regulate the expression of WT and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we observed synergy within in vitro and in vivo models of TNBC and non-small cell lung cancer, even in the absence of EGFR-activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by the WT or mutant receptor. (©2025 American Association for Cancer Research.) |
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| Grant Information: | R01CA257502 National Cancer Institute (NCI); U54 CA283766 United States CA NCI NIH HHS; T32 CA059366 United States CA NCI NIH HHS; T32GM008056 National Institute of General Medical Sciences (NIGMS); T32 GM008056 United States GM NIGMS NIH HHS; 3U54CA283766-02S2 National Cancer Institute (NCI); R21 CA288795 United States CA NCI NIH HHS; R01 CA257502 United States CA NCI NIH HHS; T32CA059366 National Cancer Institute (NCI); R50 CA221675 United States CA NCI NIH HHS; T32GM135081 National Institute of General Medical Sciences (NIGMS); T32 GM152319 United States GM NIGMS NIH HHS; R01 CA213843 United States CA NCI NIH HHS; T32GM008803 National Institute of General Medical Sciences (NIGMS); T32 GM008803 United States GM NIGMS NIH HHS; T32 GM135081 United States GM NIGMS NIH HHS |
| Substance Nomenclature: | EC 2.7.10.1 (ErbB Receptors) 0 (Protein Kinase Inhibitors) EC 2.7.10.1 (EGFR protein, human) EC 2.7.10.2 (Proto-Oncogene Proteins c-yes) EC 2.7.10.2 (YES1 protein, human) |
| Entry Date(s): | Date Created: 20250123 Date Completed: 20250502 Latest Revision: 20260610 |
| Update Code: | 20260611 |
| PubMed Central ID: | PMC12048259 |
| DOI: | 10.1158/1541-7786.MCR-24-0309 |
| PMID: | 39847459 |
| Βάση Δεδομένων: | MEDLINE |
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