Low-Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer.

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  • Additional Information
    • Source:
      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
    • Publication Information:
      Publication: Baltimore, Md. : American Association for Cancer Research
      Original Publication: Chicago [etc.]
    • Subject Terms:
      Triple Negative Breast Neoplasms*/pathology ; Triple Negative Breast Neoplasms*/drug therapy ; Triple Negative Breast Neoplasms*/metabolism ; Triple Negative Breast Neoplasms*/genetics ; Cyclin E*/metabolism ; Cyclin E*/genetics ; CDC2 Protein Kinase*/metabolism ; CDC2 Protein Kinase*/genetics; Humans ; Female ; Animals ; Mice ; Cell Line, Tumor ; Xenograft Model Antitumor Assays ; Phosphorylation ; Molecular Weight ; Cell Proliferation ; Apoptosis ; Membrane Proteins ; Protein-Tyrosine Kinases ; Protein Serine-Threonine Kinases
    • Abstract:
      Cyclin E is a regulatory subunit of CDK2 that mediates S phase entry and progression. The cleavage of full-length cyclin E (FL-cycE) to low-molecular weight isoforms (LMW-E) dramatically alters substrate specificity, promoting G1-S cell cycle transition and accelerating mitotic exit. Approximately 70% of triple-negative breast cancers (TNBC) express LMW-E, which correlates with poor prognosis. PKMYT1 also plays an important role in mitosis by inhibiting CDK1 to block premature mitotic entry, suggesting it could be a therapeutic target in TNBC expressing LMW-E. In this study, analysis of tumor samples of patients with TNBC revealed that coexpression of LMW-E and PKMYT1-catalyzed CDK1 phosphorylation predicted poor response to neoadjuvant chemotherapy. Compared with FL-cycE, LMW-E specifically upregulates PKMYT1 expression and protein stability, thereby increasing CDK1 phosphorylation. Inhibiting PKMYT1 with the selective inhibitor RP-6306 (lunresertib) elicited LMW-E-dependent antitumor effects, accelerating premature mitotic entry, inhibiting replication fork restart, and enhancing DNA damage, chromosomal breakage, apoptosis, and replication stress. Importantly, TNBC cell line xenografts expressing LMW-E showed greater sensitivity to RP-6306 than tumors with empty vector or FL-cycE. Furthermore, RP-6306 exerted tumor suppressive effects in LMW-E transgenic murine mammary tumors and patient-derived xenografts of LMW-E-high TNBC but not in the LMW-E null models examined in parallel. Lastly, transcriptomic and immune profiling demonstrated that RP-6306 treatment induced interferon responses and T-cell infiltration in the LMW-E-high tumor microenvironment, enhancing the antitumor immune response. These findings highlight the LMW-E/PKMYT1/CDK1 regulatory axis as a promising therapeutic target in TNBC, providing the rationale for further clinical development of PKMYT1 inhibitors in this aggressive breast cancer subtype. Significance: PKMYT1 upregulation and CDK1 phosphorylation in triple-negative breast cancer expressing low-molecular weight cyclin E leads to suboptimal responses to chemotherapy but sensitizes tumors to PKMYT1 inhibitors, proposing a personalized treatment strategy.
      (©2024 American Association for Cancer Research.)
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    • Grant Information:
      RP180712 Cancer Prevention and Research Institute of Texas (CPRIT); P30CA016672 National Cancer Institute (NCI); RP210028 Cancer Prevention and Research Institute of Texas (CPRIT); CA255960 National Cancer Institute (NCI); R01 CA255960 United States CA NCI NIH HHS; R01 CA223772 United States CA NCI NIH HHS
    • Accession Number:
      0 (Cyclin E)
      EC 2.7.11.22 (CDC2 Protein Kinase)
      EC 2.7.11.1 (PKMYT1 protein, human)
      EC 2.7.11.22 (CDK1 protein, human)
      0 (Membrane Proteins)
      EC 2.7.10.1 (Protein-Tyrosine Kinases)
      EC 2.7.11.1 (Protein Serine-Threonine Kinases)
    • Publication Date:
      Date Created: 20240826 Date Completed: 20241116 Latest Revision: 20241117
    • Publication Date:
      20241118
    • Accession Number:
      PMC11567801
    • Accession Number:
      10.1158/0008-5472.CAN-23-4130
    • Accession Number:
      39186665