Publication Date
10-1-2024
Journal
Molecular Cancer Therapeutics
DOI
10.1158/1535-7163.MCT-23-0564
PMID
38781103
PMCID
PMC11443213
PubMedCentral® Posted Date
5-23-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Humans, Breast Neoplasms, Female, Cyclin-Dependent Kinase 4, Animals, Mice, Cyclin-Dependent Kinase 6, Drug Resistance, Neoplasm, Protein Kinase Inhibitors, Xenograft Model Antitumor Assays, Cell Line, Tumor, Biomarkers, Tumor, Piperazines, Pyridines, Receptors, Estrogen, Gemcitabine, Protein-Tyrosine Kinases, Apoptosis
Abstract
Endocrine therapies (ET) with cyclin-dependent kinase 4/6 (CDK4/6) inhibition are the standard treatment for estrogen receptor-α-positive (ER+) breast cancer, however drug resistance is common. In this study, proteogenomic analyses of patient-derived xenografts (PDXs) from patients with 22 ER+ breast cancer demonstrated that protein kinase, membrane-associated tyrosine/threonine one (PKMYT1), a WEE1 homolog, is estradiol (E2) regulated in E2-dependent PDXs and constitutively expressed when growth is E2-independent. In clinical samples, high PKMYT1 mRNA levels associated with resistance to both ET and CDK4/6 inhibition. The PKMYT1 inhibitor lunresertib (RP-6306) with gemcitabine selectively and synergistically reduced the viability of ET and palbociclib-resistant ER+ breast cancer cells without functional p53. In vitro the combination increased DNA damage and apoptosis. In palbociclib-resistant, TP53 mutant PDX-derived organoids and PDXs, RP-6306 with low-dose gemcitabine induced greater tumor volume reduction compared to treatment with either single agent. Our study demonstrates the clinical potential of RP-6306 in combination with gemcitabine for ET and CDK4/6 inhibitor resistant TP53 mutant ER+ breast cancer.
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