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Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.

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Τίτλος: Targeting YES1 Disrupts Mitotic Fidelity and Potentiates the Response to Taxanes in Triple-Negative Breast Cancer.
Συγγραφείς: Piemonte KM; Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio.; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Ingles NN; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, Ohio., Weber-Bonk KL; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Valentine MJ; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Majmudar PR; Department of Pharmacology, Case Western Reserve University School of Medicine, Cleveland, Ohio.; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Singh S; Center for Immunotherapy and Precision Immuno-oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio., Keri RA; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Center for Immunotherapy and Precision Immuno-oncology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio.; Molecular Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio.; Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio.
Πηγή: Cancer research [Cancer Res] 2024 Nov 04; Vol. 84 (21), pp. 3556-3573.
Τύπος έκδοσης: Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural
Γλώσσα: English
Στοιχεία περιοδικού: Publisher: American Association for Cancer Research Country of Publication: United States NLM ID: 2984705R Publication Model: Print Cited Medium: Internet ISSN: 1538-7445 (Electronic) Linking ISSN: 00085472 NLM ISO Abbreviation: Cancer Res Subsets: MEDLINE
Imprint Name(s): Publication: Baltimore, Md. : American Association for Cancer Research
Original Publication: Chicago [etc.]
Ιατρικοί όροι (MeSH): Triple Negative Breast Neoplasms*/drug therapy , Triple Negative Breast Neoplasms*/pathology , Triple Negative Breast Neoplasms*/genetics , Triple Negative Breast Neoplasms*/metabolism , Mitosis*/drug effects , Forkhead Box Protein M1*/metabolism , Forkhead Box Protein M1*/genetics , Taxoids*/pharmacology , Proto-Oncogene Proteins c-yes*/genetics , Proto-Oncogene Proteins c-yes*/metabolism , Xenograft Model Antitumor Assays*, Centrosome/drug effects ; Centrosome/metabolism ; Gene Expression Regulation, Neoplastic/drug effects ; Chromosomal Instability/drug effects ; Humans ; Female ; Mice ; Animals ; Cell Line, Tumor
Περίληψη: Clinical trials examining broad-spectrum Src family kinase (SFK) inhibitors revealed significant dose-limiting toxicities, preventing advancement for solid tumors. SFKs are functionally heterogeneous, thus targeting individual members is a potential strategy to elicit antitumor efficacy while avoiding toxicity. Here, we identified that YES1 is the most highly overexpressed SFK in triple-negative breast cancer (TNBC) and is associated with poor patient outcomes. Disrupting YES1, genetically or pharmacologically, induced aberrant mitosis, centrosome amplification, multipolar spindles, and chromosomal instability. Mechanistically, YES1 sustained FOXM1 protein levels and elevated expression of FOXM1 target genes that control centrosome function and are essential for effective and accurate mitotic progression. In both in vitro and in vivo TNBC models, YES1 suppression potentiated the efficacy of taxanes, cornerstone drugs for TNBC that require elevated chromosomal instability for efficacy. Clinically, elevated expression of YES1 was associated with worse overall survival of patients with TNBC treated with taxane and anthracycline combination regimens. Together, this study demonstrates that YES1 is an essential regulator of genome stability in TNBC that can be leveraged to improve taxane efficacy.  Significance: YES1 is a sentinel regulator of genomic maintenance that controls centrosome homeostasis and chromosome stability through FOXM1, revealing this pathway as a therapeutic vulnerability for enhancing taxane efficacy in triple-negative breast cancer.
(©2024 American Association for Cancer Research.)
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Grant Information: TL1TR002549 National Center for Advancing Translational Sciences (NCATS); R01 CA213843 United States CA NCI NIH HHS; TL1 TR002549 United States TR NCATS NIH HHS; Velosano for the Cure; T32GM007250 National Institute of General Medical Sciences (NIGMS); P30 CA043703 United States CA NCI NIH HHS; T32 CA059366 United States CA NCI NIH HHS; R01 CA206505 United States CA NCI NIH HHS; T32CA059366 National Cancer Institute (NCI); T32 GM007250 United States GM NIGMS NIH HHS; R01 CA257502 United States CA NCI NIH HHS; R01CA206505 National Cancer Institute (NCI)
Molecular Sequence: GEO GSE232632; GSE267426; GSE25055; GSE96058; GSE81538
Substance Nomenclature: 0 (Forkhead Box Protein M1)
0 (Taxoids)
0 (FOXM1 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: 20240722 Date Completed: 20241104 Latest Revision: 20260716
Update Code: 20260716
PubMed Central ID: PMC11534525
DOI: 10.1158/0008-5472.CAN-23-2558
PMID: 39037997
Βάση Δεδομένων: MEDLINE
Περιγραφή
ISSN:1538-7445
DOI:10.1158/0008-5472.CAN-23-2558