Language
English
Publication Date
5-1-2024
Journal
Clinical Cancer Research
DOI
10.1158/1078-0432.CCR-23-2975
PMID
38381406
PMCID
PMC11061603
PubMedCentral® Posted Date
2-21-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Purpose: Resistance to endocrine therapy (ET) and CDK4/6 inhibitors (CDK4/6i) is a clinical challenge in estrogen receptor (ER)-positive (ER+) breast cancer. Cyclin-dependent kinase 7 (CDK7) is a candidate target in endocrine-resistant ER+ breast cancer models and selective CDK7 inhibitors (CDK7i) are in clinical development for the treatment of ER+ breast cancer. Nonetheless, the precise mechanisms responsible for the activity of CDK7i in ER+ breast cancer remain elusive. Herein, we sought to unravel these mechanisms.
Experimental design: We conducted multi-omic analyses in ER+ breast cancer models in vitro and in vivo, including models with different genetic backgrounds. We also performed genome-wide CRISPR/Cas9 knockout screens to identify potential therapeutic vulnerabilities in CDK4/6i-resistant models.
Results: We found that the on-target antitumor effects of CDK7 inhibition in ER+ breast cancer are in part p53 dependent, and involve cell cycle inhibition and suppression of c-Myc. Moreover, CDK7 inhibition exhibited cytotoxic effects, distinctive from the cytostatic nature of ET and CDK4/6i. CDK7 inhibition resulted in suppression of ER phosphorylation at S118; however, long-term CDK7 inhibition resulted in increased ER signaling, supporting the combination of ET with a CDK7i. Finally, genome-wide CRISPR/Cas9 knockout screens identified CDK7 and MYC signaling as putative vulnerabilities in CDK4/6i resistance, and CDK7 inhibition effectively inhibited CDK4/6i-resistant models.
Conclusions: Taken together, these findings support the clinical investigation of selective CDK7 inhibition combined with ET to overcome treatment resistance in ER+ breast cancer. In addition, our study highlights the potential of increased c-Myc activity and intact p53 as predictors of sensitivity to CDK7i-based treatments.
Keywords
Humans, Breast Neoplasms, Female, Drug Resistance, Neoplasm, Apoptosis, Animals, Mice, Receptors, Estrogen, Cyclin-Dependent Kinase-Activating Kinase, Cyclin-Dependent Kinases, Proto-Oncogene Proteins c-myc, Protein Kinase Inhibitors, Signal Transduction, Cell Cycle, Xenograft Model Antitumor Assays, Cell Line, Tumor, Cell Proliferation, Gene Expression Regulation, Neoplastic, Cyclin-Dependent Kinase 4, CRISPR-Cas Systems
Published Open-Access
yes
Recommended Citation
Guarducci, Cristina; Nardone, Agostina; Russo, Douglas; et al., "Selective CDK7 Inhibition Suppresses Cell Cycle Progression and MYC Signaling While Enhancing Apoptosis in Therapy-resistant Estrogen Receptor-positive Breast Cancer" (2024). Faculty and Staff Publications. 3959.
https://digitalcommons.library.tmc.edu/baylor_docs/3959