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

// Giancarlo Barone 1, * , Arvind Arora 2, * , Anil Ganesh 1 , Tarek Abdel-Fatah 2 , Paul Moseley 2 , Reem Ali 2 , Stephen YT Chan 2 , Constantinos Savva 2 , Kristina Schiavone 1 , Natasha Carmell 1 , Katie N. Myers 1 , Emad A. Rakha 2 , Srinivasan Madhusudan 2 and Spencer J. Collis 1 1 Sheffield Institute for Nucleic Acids (SInFoNiA), Academic Unit of Molecular Oncology, Department of Oncology and Metabolism, University of Sheffield Medical School, Sheffield, UK 2 Academic Unit of Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, UK * These authors contributed equally to this work Correspondence to: Spencer J. Collis, email: s.collis@sheffield.ac.uk Srinivasan Madhusudan, email: srinivasan.madhusudan@nottingham.ac.uk Keywords: CDK18; breast cancer; replication stress; chemotherapy; cyclin-dependent kinase Received: June 06, 2018      Accepted: June 13, 2018      Published: June 29, 2018 ABSTRACT Background: Cyclin-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. Results: High 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. Conclusions: These 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 Methods: CDK18 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.