Cancer Therapeutics Insights Chk1/2 Inhibition Overcomes the Cisplatin Resistance of Head and Neck Cancer Cells Secondary to the Loss of Functional p53

Despite the use ofmultimodality therapy using cisplatin to treat patientswith advanced stage squamous cell carcinoma of the head and neck (HNSCC), there is an unacceptably high rate of treatment failure. TP53 is the most commonlymutated gene inHNSCC, and the impact of p53mutation on response to cisplatin treatment is poorly understood. Here, we show unambiguously that wild-type TP53 (wtp53) is associated with sensitivity of HNSCC cells to cisplatin treatment, whereasmutation or loss of TP53 is associatedwith cisplatin resistance. Wealso show that senescence is themajor cellular response to cisplatin inwtp53HNSCCcells and that cisplatin resistance in p53-null or -mutant TP53 cells is due to their lack of senescence. Given the dependence on checkpoint kinase (Chk)1/2 kinases to mediate the DNA damage response in p53-deficient cells, there is potential to exploit this to therapeutic advantage through targeted inhibition of the Chk1/2 kinases. Treatment of p53-deficientHNSCC cellswith theChk inhibitorAZD7762 sensitizes them to cisplatin through induction of mitotic cell death. This is the first report showing the ability of a Chk kinase inhibitor to sensitize TP53-deficient HNSCC to cisplatin in a synthetic lethalmanner, which has significance given the frequency of TP53mutations in this disease and because cisplatin has becomepart of standard therapy for aggressiveHNSCC tumors. These preclinical data provide evidence that a personalized approach to the treatment of HNSCC based on Chk inhibition in p53-mutant tumors may be feasible. Mol Cancer Ther; 12(9); 1860–73. 2013 AACR.