The relationship of CDK18 expression in breast cancer to clinicopathological parameters and therapeutic response

Abstract

BackgroundCyclin-Dependent Kinases (CDKs) are established anti-cancer drug targets and a new generation of CDK inhibitors are providing clinical benefits to a sub-set of breast cancer patients. We have recently shown that human CDK18 promotes efficient cellular responses to replication stress. In the current study, we have investigated the clinicopathological and functional significance of CDK18 expression levels in breast cancers.ResultsHigh CDK18 protein expression was associated with a triple negative and basal-like phenotype (p = 0.021 and 0.027 respectively) as well as improved patient survival, which was particularly significant in ER negative breast cancers (n = 594, Log Rank 6.724, p = 0.01) and those treated with chemotherapy (n = 270, Log Rank 4.575, p = 0.03). In agreement with these clinical findings, breast cancer cells genetically manipulated using a dCRISPR approach to express high levels of endogenous CDK18 exhibited an increased sensitivity to replication stress-inducing chemotherapeutic agents, as a consequence to defective replication stress signalling at the molecular level.ConclusionsThese data reveal that CDK18 protein levels may predict breast cancer disease progression and response to chemotherapy, and provide further rationale for potential targeting of CDK18 as part of novel anti-cancer strategies for human cancers.Materials and MethodsCDK18 protein expression was evaluated in 1650 breast cancers and correlated to clinicopathological parameters and survival outcomes. Similar analyses were carried out for genetic and transcriptomic changes in CDK18 within several publically available breast cancer cohorts. Additionally, we used a deactivated CRISPR/Cas9 approach (dCRISPR) to elucidate the molecular consequences of heightened endogenous CDK18 expression within breast cancer cells.

Proteomic and Transcriptomic Analysis Identify Spliceosome as a Significant Component of the Molecular Machinery in the Pituitary Tumors Derived from POU1F1- and NR5A1-Cell Lineages

“…We found that genes that participate in important events for tumorigenesis could generate alternatively-spliced isoforms. Genes participating in cell cycle progression and genome stability such as CDK18 [25] present potential isoforms in PA. Similarly, THY1 genes which participate in T-cell activation, apoptosis, cell migration, cell adhesion and extravasation [26] also present splicing generated isoforms.…”

Introductory Chapter: Gene Editing Technologies and Applications

“…Cyclin-dependent kinases (CDKs) are established anti-cancer drug targets, and a new generation of CDK inhibitors provides clinical benefits to the patients. Breast cancer cells were genetically manipulated using a deactivated CRISPRs/Cas9 (dCRISPR) approach to strengthen the endogenous CDK18 promoter to express highly to exhibit an increased sensitivity [41].…”

Keeping CDK18 in balance to prevent DNA replication stress in breast cancer

“…Another important example is constituted by CDK18, whose role was recently identified by studies in Collins laboratory [3]. Further studies in the accompanying manuscript not only identified CDK18 as an important regulator of DNA replication stress signalling, but also provided novel insights on its role in breast cancer progression [4].…”

“…High CDK18 protein expression could predict a better response to chemotherapy. These data suggest that CDK18 mRNA and protein levels are regulated differently within cancer cells with potentially distinct predictions on outcome for patients [4].…”

“…Furthermore, in cells expressing high levels of CDK18, the response to replication stress induced by limiting nucleotides was impaired. The authors observed a compromised activation of ATR signalling and corresponding increased sensitivity to DNA damaging agents impairing nucleotide production such as methotrexate or 5-FU [4].…”