Journal of Blood Disorders & Transfusion

BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors

Joint Event on Hematology, Immunology & Traditional Medicine

December 05-06, 2018 | Lisbon, Portugal

Jiri Kohoutek,Hana Paculova, Juraj Kramara, Sarka Simeckova, Karel Soucek, Ondrej Hylse ,Kamil Paruch, Marek Svoboda and Martin Mistrik

Veterinary Research Institute, Czech Republic
Palacky University, Czech Republic
The Czech Academy of Sciences, Czech Republic
St. Annes University Hospital, Czech Republic
Masaryk University, Czech Republic
Masaryk Memorial Cancer Institute, Czech Republic

Posters & Accepted Abstracts: J Blood Disord Transfus

Abstract:

Statement of the Problem: A broad spectrum of tumors develops resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly (ADP-ribose) polymerase 1/2 proteins and DNA damage response genes including BRCA1, a factor involved in homologous recombination�????mediated DNA repair and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. Inhibitors of CHK1 have been shown to enhance the anti-cancer effect of DNAdamaging compounds. Since, loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. Methodology & Theoretical Orientation: We have utilized different approaches to examine effect of CHK1 inhibitors in combination with down-regulated activity of CDK12 and BRCA1 on cell proliferation, survival, apoptosis, cell cycle and DNA-damage response pathway in various oncogenic cell lines and by employing a mouse orthotopic xenograft model. Findings: The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 down-regulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Conclusion & Significance: Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12- deficient tumors.

Biography :

Jiri Kohoutek is broadly interested in regulation of transcription in eukaryotes. He is also focused to study diverse function/s of cyclin-dependent kinases not only within the regulation of transcription during development and cellular differentiation, but also in the context of cellular physiology, such as response to given extracellular stimulus, cell response to physiological and stress induced conditions in order to develop new ways how to counteract tumor growth and invasiveness.

E-mail: kohoutek@vri.cz