CKS protein overexpression renders tumors susceptible to a chemotherapeutic strategy that protects normal tissues

// John Tat 1, 2 , Céline Loriot 1 , Martha Henze 1 , Charles Spruck 3 , Brunhilde H. Felding 1 and Steven I. Reed 1 1 Department of Molecular Medicine, The Scripps Research Institute, CA 92037, La Jolla, San Diego, USA 2 Present address: Department of Medicine, University of California, San Diego, La Jolla, 92093-0652, California, San Diego, USA 3 Tumor Initiation and Maintenance Program, Cancer Center, Sanford-Burnham-Prebys Medical Discovery Institute, La Jolla, 92037, CA, San Diego, USA Correspondence to: Steven I. Reed, email: sreed@scripps.edu Keywords: cancer chemotherapy; cyclin-dependent kinase; cyclin-dependent kinase subunit; replication stress; replication stress checkpoint Received: September 24, 2017 Accepted: November 10, 2017 Published: December 04, 2017 ABSTRACT The cyclin-dependent kinase-interacting proteins Cyclin-dependent Kinase Subunit 1 and 2 (CKS1 and 2) are frequently overexpressed in cancer and linked to increased aggressiveness and poor prognoses. We previously showed that CKS protein overexpression overrides the replication stress checkpoint activated by oncoproteins. Since CKS overexpression and oncoprotein activation/overexpression are often observed in the same tumors, we have hypothesized that CKS-mediated checkpoint override could enhance the ability of premalignant cells experiencing oncoprotein-induced replication stress to expand. This tumor advantage, however, could represent a vulnerability to exploit therapeutically. Here, we first show in vitro that CKS protein overexpression selectively sensitizes tumor-derived cell lines to nucleoside analog-mediated toxicity under replication stress conditions. A treatment combination of the nucleoside analog gemcitabine and an agent that induces replication stress (thymidine or methotrexate) resulted in selective targeting of CKS protein-overexpressing tumor-derived cells while protecting proliferative cells with low CKS protein levels from gemcitabine toxicity. We validated this strategy in vivo and observed that Cks2-overexpressing mammary tumors in nude mice were selectively sensitized to gemcitabine under conditions of methotrexate-induced replication stress. These results suggest that high CKS expression might be useful as a biomarker to identify subgroups of cancer patients who might benefit from the described therapeutic approach.