Abstract 4637: Chk1 inhibition: a promising targeted treatment for head and neck squamous cell carcinoma

Abstract

Over 90% of all malignant tumors in the head and neck region are squamous cell carcinomas (HNSCC), ranking within the top 10 of most common cancers worldwide. HNSCC arise in the mucosal linings of the upper aerodigestive tract, and known risk factors are tobacco use, excessive alcohol consumption and infection with high risk types of the human papillomavirus (HPV). Despite the application of intensive treatment protocols, the 5-years survival rate of HNSCC patients has hardly increased last decades and remained at approximately 50%. Therefore, new therapeutic possibilities are urgently awaited. Previously, we identified CHEK1 as a candidate therapeutic target for HNSCC in a whole genome siRNA screen (Martens-de Kemp et al, Clin Cancer Res 2013). Additionally, a functional screen using a microRNA expressing library indicated that knockdown of ATM expression may cause a lethal effect in HNSCC cell lines as well (Lindenbergh-van der Plas et al, Clin Cancer Res 2013). The aim of the present study was to investigate whether interference with the ATM/ATR/CHEK1/CHEK2 DNA damage response pathway is indeed a promising therapeutic approach in HNSCC. RNA interference using siRNAs targeting ATM, ATR, CHEK1 and CHEK2 confirmed that particularly CHEK1 is essential for the survival of a subset of HNSCC cell lines, whereas the cell viability of primary oral keratinocytes and fibroblasts was not compromised. This was confirmed in vitro by treatment with a small molecule inhibitor targeting Chk1, and a therapeutic window between cancer and normal oral mucosal cells was observed. Functional assays indicated an S-phase delay in Chk1 inhibited HNSCC cells, followed by DNA damage. The latter was indicated by elevated phosphorylation of ATM Ser1981 and γH2Ax Ser139, as well as the appearance of chromosomal breaks. The DNA damage response initiated caspase-mediated apoptosis, resulting in programmed cell death. In summary, our data show that HNSCC cells appear to depend strongly on a functional Chk1 protein during DNA replication. Therefore, Chk1 inhibition seems an interesting therapeutic strategy for HNSCC, at least in a subset of tumors. Citation Format: Anne M. van Harten, Marijke Stigter-van Walsum, Marijke Buijze, Boudewijn Jm Braakhuis, Ruud H. Brakenhoff. Chk1 inhibition: a promising targeted treatment for head and neck squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4637.