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Oncogene. 2019 Jan 30. doi: 10.1038/s41388-019-0708-7. [Epub ahead of print]

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

Author information

1
Oncology Translational Research, Pfizer Inc., San Diego, CA, 92121, USA.
2
Genomics Institute of the Novartis Research Foundation, San Diego, CA, 92121, USA.
3
Drug Safety Research and Development, Pfizer Inc., San Diego, CA, 92121, USA.
4
Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA.
5
Biostatistics, La Jolla Laboratories, Pfizer Inc., San Diego, CA, 92121, USA.
6
Tumor Cell Biology, Oncology Research and Development, Pfizer Inc., San Diego, CA, 92121, USA.
7
Oncology Translational Research, Pfizer Inc., San Diego, CA, 92121, USA. ping.wei@pfizer.com.

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.

PMID:
30700828
DOI:
10.1038/s41388-019-0708-7

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