Abemaciclib Is Effective Against Pancreatic Cancer Cells and Synergizes with HuR and YAP1 Inhibition.

Molecular Cancer Research : MCR
Teena DhirJonathan R Brody

Abstract

Mutation or promoter hypermethylation of CDKN2A is found in over 90% of pancreatic ductal adenocarcinomas (PDAC) and leads to loss of function of cell-cycle inhibitors p16 (INK4A) and p14 (ARF) resulting in unchecked proliferation. The CDK4/6 inhibitor, abemaciclib, has nanomolar IC50s in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell-cycle arrest, apoptosis, and the senescent phenotype detected with β-galactosidase staining and relevant mRNA elevations. Daily abemaciclib treatments in mouse PDAC xenograft studies were safe and demonstrated a 3.2-fold decrease in tumor volume compared with no treatment (P < 0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a prosurvival mRNA stability factor that regulates cyclin D1, and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional coactivator important for CDK6 and cyclin D1, were both synergistic with abemaciclib. Accordingly, siRNA oligonucleotides targeted against HuR, YAP1, and their common target cyclin D1, validated the synergy studies. In addition, we have seen increased sensitivity to abemaciclib in a PDAC cell line that harbors a loss of the ELAVL1 gene via CRI...Continue Reading

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Citations

Oct 4, 2020·Journal of Hematology & Oncology·Yunzhen QianChen Liu
Jan 6, 2021·Cancer Metastasis Reviews·Bayan Al-ShareMaria Diab
Feb 23, 2021·Advanced Drug Delivery Reviews·Talia GolanMaria Raitses-Gurevich
Mar 7, 2021·Seminars in Oncology·Aurélien LambertMichel Ducreux
Jul 27, 2021·Journal of Biochemical and Molecular Toxicology·Zeynep OzmanMehmet R Sekeroglu
Aug 28, 2021·Life·Graziana DigiacomoAndrea Cavazzoni

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