Pan-cancer analysis reveals synergistic effects of CDK4/6i and PARPi combination treatment in RB-proficient and RB-deficient breast cancer cells

摘要

Diagram showing the possible relationships among DNA damage, PARPs, DRPCC, and mutation. In detail, DNA damage and mutations are closely related (Formula 1). As both DRPCC(s) and PARP are involved in DNA repair, it is logical to suppose that cancer cells with decreased activity of DRPCC(s) and/or PARP should be biased toward acquiring more mutations (Formula 2 and 3). Moreover, cancer cells are often reliant on increased activity of PARP and/or DRPCC(s) to survive extra DNA damage from enhanced mutagenic pathway(s) and/or decreased DNA repair pathway(s) (Formula 4 and 5). Considering that PARPs are sensors of DNA damage and broadly involved in multiple DNA repair pathways, we reasoned that the combined inhibition of PARPs and DRPCC(s) should show synergy (Formula 7–9). Schematic showing the pipeline used for the prediction of DRPCC(s) and drug target(s). Summary statistics for the 27 different cancer types in this study. , All mutations ( ), missense mutations ( ), and sense mutations ( ) across 27 cancer types. Each data point represents one tumor sample, and the axis is log transformed for better data visualization. Red, orange, or blue horizontal bars indicate the average mutation load. The -scores for mRNA expression were calculated for each sample by comparing them RNA expression of a gene to the distribution in a reference population that represents typical expression for the gene. The returned value ( -score) indicates the number of standard deviations away from the mean of expression in the reference population. Scatter plots showing the correlation between the ranks of mutation load and gene expression. Each data point represents one tumor sample. Data of TP53, BRCA2, and PAPR2 are from BLCA, LGG, and ACC, respectively. The red dashed line is the best fit for visualization. Summary statistics for positive and negative genes across 27 cancer types. Heatmap depicting the enrichment of positive (left) and negative (right) genes, respectively.