Combining CDK4/6 inhibition with taxanes enhances anti-tumor efficacy by sustained impairment of pRB-E2F pathways in squamous cell lung cancer View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2019-01-30

AUTHORS

Joan Cao, Zhou Zhu, Hui Wang, Timothy C. Nichols, Goldie Y. L. Lui, Shibing Deng, Paul A. Rejto, Todd VanArsdale, James S. Hardwick, Scott L. Weinrich, Ping Wei

ABSTRACT

The CDK4/6 inhibitor palbociclib reduces tumor growth by decreasing retinoblastoma (RB) protein phosphorylation and inducing cell cycle arrest at the G1/S phase transition. Palbociclib in combination with anti-hormonal therapy brings significant benefit to breast cancer patients. In this study, novel combination approaches and underlying molecular/cellular mechanisms for palbociclib were explored in squamous cell lung cancer (SqCLC), the second most common subtype of non-small cell lung cancer. While approximate 20% lung patients benefit from immunotherapy, most SqCLC patients who receive platinum-doublet chemotherapy as first-line treatment, which often includes a taxane, are still in need of more effective combination therapies. Our results demonstrated enhanced cytotoxicity and anti-tumor effect with palbociclib plus taxanes at clinically achievable doses in multiple SqCLC models with diverse cancer genetic backgrounds. Comprehensive gene expression analysis revealed a sustained disruption of pRB-E2F signaling by combination that was accompanied with enhanced regulation of pleiotropic biological effects. These included several novel mechanisms such as abrogation of G2/M and mitotic spindle assembly checkpoints, as well as impaired induction of hypoxia-inducible factor 1 alpha (HIF-1α). The decrease in HIF-1α modulated a couple key angiogenic and anti-angiogenic factors, resulting in an enhanced anti-angiogenic effect. This preclinical work suggests a new therapeutic opportunity for palbociclib in lung and other cancers currently treated with taxane based chemotherapy as standard of care. More... »

PAGES

4125-4141

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/s41388-019-0708-7

DOI

http://dx.doi.org/10.1038/s41388-019-0708-7

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1111776890

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/30700828


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