Faculty, Staff and Student Publications
Publication Date
12-30-2024
Journal
Nature Communications
Abstract
Metaplastic breast cancer (MpBC) is a highly chemoresistant subtype of breast cancer with no standardized therapy options. A clinical study in anthracycline-refractory MpBC patients suggested that nitric oxide synthase (NOS) inhibitor NG-monomethyl-l-arginine (L-NMMA) may augment anti-tumor efficacy of taxane. We report that NOS blockade potentiated response of human MpBC cell lines and tumors to phosphoinositide 3-kinase (PI3K) inhibitor alpelisib and taxane. Mechanistically, NOS blockade leads to a decrease in the S-nitrosylation of c-Jun NH2-terminal kinase (JNK)/c-Jun complex to repress its transcriptional output, leading to enhanced tumor differentiation and associated chemosensitivity. As a result, combined NOS and PI3K inhibition with taxane targets MpBC stem cells and improves survival in patient-derived xenograft models relative to single-/dual-agent therapy. Similarly, biopsies from MpBC tumors that responded to L-NMMA+taxane therapy showed a post-treatment reversal of epithelial-to-mesenchymal transition and decreased stemness. Our findings suggest that combined inhibition of iNOS and PI3K is a unique strategy to decrease chemoresistance and improve clinical outcomes in MpBC.
Keywords
Humans, Female, Breast Neoplasms, Animals, Cell Line, Tumor, Phosphoinositide-3 Kinase Inhibitors, Taxoids, Mice, Xenograft Model Antitumor Assays, Bridged-Ring Compounds, Drug Resistance, Neoplasm, Nitric Oxide Synthase, Phosphatidylinositol 3-Kinases, JNK Mitogen-Activated Protein Kinases, Metaplasia, Proto-Oncogene Proteins c-jun, Thiazoles
DOI
10.1038/s41467-024-54651-x
PMID
39737957
PMCID
PMC11685991
PubMedCentral® Posted Date
12-30-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Genetic Phenomena Commons, Medical Genetics Commons, Oncology Commons