Language
English
Publication Date
8-27-2025
Journal
Science Translational Medicine
DOI
10.1126/scitranslmed.adq5492
PMID
40864686
PMCID
PMC12697068
PubMedCentral® Posted Date
12-12-2025
PubMedCentral® Full Text Version
Author MSS
Abstract
Neurofibromin/NF1 is a RAS (rat sarcoma virus) GTPase activating protein and estrogen receptor (ER) transcriptional corepressor. NF1low status, identified by copy number loss or low mRNA/protein expression is associated with endocrine therapy resistance in approximately 20% of ER+/HER2− (human epidermal growth factor receptor 2) early-stage breast cancers. The identification of targeted treatments for NF1low ER+/HER2− breast cancer is therefore a priority. In this study proteogenomic analysis of ER+/HER2− breast cancer demonstrated that NF1low tumors exhibited elevated cyclin-dependent kinase 4/6 (CDK4/6) activity. In cell lines, NF1-deletion had a dual effect on CDK4 activity. First, by promoting ER recruitment to CCND1 (cyclin D1), thereby increasing CDK4-cyclin D1 complex formation and second, through C-RAF (rapidly accelerated fibrosarcoma) activation which drove phosphorylation of the CDK4 activation-loop. Preclinical modelling demonstrated that NF1low ER+ cancer cells were more sensitive to fulvestrant combined with a CDK4/6 inhibitor (CDK4/6i) versus fulvestrant alone, with the induction of cell-death in vitro, and durable tumor regressions in ER+ NF1low patient-derived xenograft models in vivo. Furthermore, NF1low ER+/HER2− tumors were more sensitive to neoadjuvant aromatase inhibitor (AI) plus palbociclib compared to neoadjuvant AI alone, as indicated by suppression of mRNA-based proliferation scores. These data are consistent with a model whereby that ER and RAS co-activation upon NF1-loss can drive CDK4/6 activity and endocrine therapy resistance but renders NF1low ER+ tumors susceptible to CDK4/6 inhibition. Development of clinical-grade NF1 diagnostics should be prioritized to determine whether NF1low ER+ breast cancers should receive adjusted adjuvant treatment recommendations that reflect increased responsiveness to CDK4/6i inhibition.
Keywords
Humans, Cyclin-Dependent Kinase 4, Breast Neoplasms, Cyclin-Dependent Kinase 6, Female, Receptors, Estrogen, Animals, Neurofibromin 1, Protein Kinase Inhibitors, Cell Line, Tumor, Mice, Piperazines, Pyridines, Xenograft Model Antitumor Assays, Cyclin D1, Cell Proliferation
Published Open-Access
yes
Recommended Citation
Zheng, Ze-Yi; Chen, Anran; Jaehnig, Eric J; et al., "NF1-Depleted Er+ Breast Cancers Are Differentially Sensitive to CDK4/6 Inhibitors" (2025). Faculty, Staff and Students Publications. 6270.
https://digitalcommons.library.tmc.edu/baylor_docs/6270