Coordinate Up-regulation of Both TK1 and TS Expression in Cycling Cells: Mechanistic Basis and Implications for Dual-Targeted Cancer Therapy

Abstract Our previous study [2] has revealed that various types of cycling cells undergo rapid proliferation and division. Cycling cells can be broadly categorized into two groups: cycling immune cells (CICs) and cycling non-immune cells (CNICs). Cancer cells represent a special type of cycling cells. Based on a set of 26 marker genes, we proposed a simple method for the rapid identification of cycling-cell types. Comparisons across cycling-cell types uncovered novel gene-regulatory mechanisms underlying the cell cycle, development, and differentiation. Notably, we discovered that the coordinate up-regulation of both TS and TK1 expression is indispensable for securing a robust deoxythymidine triphosphate (dTTP) supply required for DNA replication in cycling cells. The compensatory interplay between salvage and de novo synthesis provides a plausible explanation for resistance to 5-fluorouracil (5-FU), a TS inhibitor for cancer chemotherapy. Consequently, blocking dTTP synthesis requires co-inhibition of TK1 and TS. For the first time, we present the crucial single-cell transcriptome evidence for this coordinate up-regulation, thereby establishing the mechanistic basis for developing TK1/TS as a dual target in cancer therapy.