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

Abstract

Despite the use of multimodality therapy employing cisplatin to treat patients with advanced stage head and neck squamous cell carcinoma (HNSCC), there is an unacceptably high rate of treatment failure. TP53 is the most commonly mutated gene in HNSCC, and the impact of p53 mutation 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 while mutation or loss of TP53 is associated with cisplatin resistance. We also demonstrate that senescence is the major cellular response to cisplatin in wtp53 HNSCC cells and that cisplatin resistance in p53 null or mutant TP53 cells is due to their lack of senescence. Given the dependence on Chk1/2 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 deficient HNSCC cells with the Chk inhibitor AZD7762 sensitizes them to cisplatin through induction of mitotic cell death. This is the first report demonstrating the ability of a Chk kinase inhibitor to sensitize TP53-deficient HNSCC to cisplatin in a synthetic lethal manner, which has significance given the frequency of TP53 mutations in this disease and because cisplatin has become part of standard therapy for aggressive HNSCC tumors. These pre-clinical data provide evidence that a personalized approach to the treatment of HNSCC based on Chk inhibition in p53 mutant tumors may be feasible.

Chk1-induced CCNB1 overexpression promotes cell proliferation and tumor growth in human colorectal cancer

“…16 Chk1 is an essential kinase in governing cell cycle G 1 /S, S, and G 2 /M phase checkpoints and determining cellular responses to DNA damage. [22][23][24][25][26] In contrast to the well-known utility of Chk1 inhibitors in sensitizing tumors to chemotherapy agents, 23,27,28 Chk1 overexpression or downexpression also occurs in some types of tumors, including breast cancer, ovarian cancer, cervical cancer, and neuroblastoma. 22,[29][30][31][32][33] In our study, we found Chk1 mRNA and protein levels were upregulated in colorectal cancer tissues compared with paired normal tissues, and positively correlated with CCNB1 expression.…”

Candidate synthetic lethality partners to PARP inhibitors in the treatment of ovarian clear cell cancer

“…Simultaneous inhibition of ERBB2 and NOTCH1 also uncovers a synthetic lethal relationship (59). DNA damage or the presence of unreplicated DNA induces cell cycle arrest in G2/M phase in a manner regulated by CHEK1 in CCC cells overexpressing HNF-1β (60). CHEK1 is reportedly a synthetic lethality partner of ATR, MYC, TP53, WEE1 G2 checkpoint kinase (WEE1), or cyclin-dependent kinase inhibitor 1A (CDKN1A), also known as p21…”

Exploiting Senescence for Cancer Treatment

“…It has also been reported that the dose strength of genotoxic therapy influences the choice of cellular response pathways in cancer cells. For example, we have shown that supraphysiological dose of cisplatin leads to apoptosis in head and neck squamous cell carcinoma (HNSCC) cells regardless of p53 status; however, a physiological cisplatin dose leads to robust senescence response in wild type p53 HNSCC cells [23]. Advanced malignancies frequently harbor epigenetic silencing, losses, or mutations in the genes critical for TIS pathway induction.…”