Investigations on Cancer Cell Biological Effects of CDK8 Inhibitor Q-12

Author

Zhixin Lu, University of the PacificFollow

Date of Award

2018

Document Type

Thesis

Degree Name

Master of Science (M.S.)

Department

Pharmaceutical and Chemical Sciences

First Advisor

Wade A. Russu

First Committee Member

William R. Chan

Second Committee Member

Linda L. Norton

Abstract

Over the past two decades, protein kinases have been intensively investigated as targets to treat neoplastic diseases. Many protein kinase inhibitors not only have therapeutic potential but are becoming invaluable reagents for the study of cell signaling.

We aspired to use our Cyclin-Dependent Kinase 8 inhibitor, Q-12, as a probe for biomarker discovery for CDK8 inhibitor sensitive tumor types. Q-12 shows potent inhibition of cell viability and induction of apoptosis process in some triple-negative breast cancer and colorectal cancer cell lines in vitro. Western blot results indicate that the reduction of STAT1 phosphorylation could be a robust indicator of CDK8 target engagement in all three cancer cell lines used upon Q-12 treatment. Q-12 treatment of triple-negative breast cancer cell line (MDA-MB-468) decreases STAT1 phosphorylation but increases STAT3 phosphorylation. Q-12 activity in MDA-MB-468 cell is dependent

on the activation of STAT3 phosphorylation. All results suggest that there may be a critical STAT1 to STAT3 ratio that may serve as a biomarker for CDK8 inhibitor sensitivity. In this precision medicine era, the discovery of biomarker is urgently needed to minimize the risks of severe side-effects by traditional chemotherapy and improve diagnosis and monitor therapy response across a wide spectrum of disease, especially heterogenous type of disease, like cancer.

Pages

50

Recommended Citation

Lu, Zhixin. (2018). Investigations on Cancer Cell Biological Effects of CDK8 Inhibitor Q-12. University of the Pacific, Thesis. https://scholarlycommons.pacific.edu/uop_etds/3554