Figure 6. Gaining chromosome 1q increases sensitivity to UCK2 substrates.

(A) A schematic of the metabolism of two pyrimidine analogs, RX-3117 and 3-deazauridine. UCK2, a kinase encoded on chromosome 1q, phosphorylates these compounds to produce cytotoxic derivatives that can poison DNA and RNA synthesis.

(B) Boxplots displaying the expression of UCK2 from the cancer cell line encyclopedia (left) and TCGA (right), divided based on the copy number of chromosome 1q. The boxplots represent the 25th, 50th, and 75th percentiles of the indicated data, while the whiskers represent the 10th and 90th percentiles of the indicated data. Data were analyzed using unpaired t-tests; n = 10,331 samples from TCGA and 942 samples from CCLE.

(C) Expression of UCK2 protein in cancer cell lines with 1q trisomies or following aneuploidy-elimination.

(D) Cellular sensitivity of A2780 and MCF10A treated with different concentrations of RX-3117 or 3-deazauridine. Mean ± SEM, data from representative trials are shown (n ≥ 3 total trials).

(E) A schematic displaying cellular competition between trisomic and disomic cells. Under normal conditions, certain trisomies enhance cellular fitness, allowing these cells to overtake the population and enhance malignant growth (top). However, treatment with an “anti-trisomy” compound could selectively impair the growth of the aneuploid cells, keeping the population in a low-malignant state (bottom).

(F) A cellular competition between fluorescently-labeled MCF10A 1q-trisomic and unlabeled 1q-disomic cells. These cells were mixed at a ratio of 20% to 80% and then cultured in either DMSO or 3-deazauridine. While the trisomic cells quickly dominate the population in drug-free medium, treatment with 3-deazauridine prevents the outgrowth of the 1q-trisomic subpopulation. Data from representative trial are shown (n = 2 total trials).

*p < 0.05, ** p < 0.005, *** p < 0.0005