Abstract
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 mode of cell death that accounts for the cisplatin responses in wtp53 HNSCC cells and that cisplatin resistance in p53 null or mutant TP53 cells is due their resistance to senescence induction. 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 leads to sensitization to cisplatin treatment through the induction of mitotic cell death. Therefore, the most common genomic alteration in HNSCC, p53 mutation, can lead to a decreased therapeutic response to cisplatin that can be overcome using a synthetic lethal approach with Chk inhibition. 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. The is the first report presenting unambiguous evidence that HNSCC cells respond to cisplatin in a p53 dependent manner. In addition, we clarify that in the presence of wtp53 the major mode of cell death in response to cisplatin in HNSCC cells is senescence, and not apoptosis. TP53 mutations have been identified in 60% of HNSCC cases and many of these patients’ tumors are resistant non-surgical treatment options. By showing dramatic sensitization to cisplatin through addition of Chk1/2 kinase inhibitor in cells with different HNSCC p53 mutations, we present a promising therapeutic approach that warrants further pre-clinical and clinical investigation. Citation Format: Mayur A. Gadhikar, Maria Rita Sciuto, Marcus Vinicus Alves Ortega, Curtis Pickering, Marcus Monroe, Abdullah Osman, David Neskey, Erich M. Sturgis, Jeffrey N. Myers, Mitchell J. Frederick. Overcoming the cisplatin resistance of HNSCC cells through Chk1/2 inhibition. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 708. doi:10.1158/1538-7445.AM2013-708
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.