Our hypothesis that the signaling pathway heterogeneity of cellular response to DSBs might determine chemotherapeutic sensitivity of cancer cells is evidenced in this study, and our major finding is that cancer cells (e.g., H1299) lacking ATM-CHK2-p53-p21 mediated G1 checkpoint and p53-dependent DNA repair are much more sensitive to chemotherapeutics. Here, CDKN1A is linked to cancer.