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

Authors

Mi Li
Amriti R Lulla
Yan Wang
Spyros Tsavaschidis
Fuchenchu Wang
Cansu Karakas
Tuyen D T Nguyen
Tuyen N Bui
Marc A Pina
Mei-Kuang Chen
Sofia Mastoraki
Asha S Multani
Natalie W Fowlkes
Aysegul Sahin
C Gary Marshall
Kelly K Hunt
Khandan Keyomarsi

Publication Date

11-15-2024

Journal

Cancer Research

DOI

10.1158/0008-5472.CAN-23-4130

PMID

39186665

PMCID

PMC11567801

PubMedCentral® Posted Date

5-15-2025

PubMedCentral® Full Text Version

Post-print

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.

Keywords

Triple Negative Breast Neoplasms, Humans, Female, Animals, Mice, Cyclin E, CDC2 Protein Kinase, Cell Line, Tumor, Xenograft Model Antitumor Assays, Phosphorylation, Molecular Weight, Cell Proliferation, Apoptosis, Membrane Proteins, Protein-Tyrosine Kinases, Protein Serine-Threonine Kinases

Published Open-Access

yes

Recommended Citation

Li, Mi; Lulla, Amriti R; Wang, Yan; et al., "Low-Molecular Weight Cyclin E Confers a Vulnerability to PKMYT1 Inhibition in Triple-Negative Breast Cancer" (2024). Faculty, Staff and Student Publications. 4381.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/4381