Abstract
Head and neck squamous cell carcinoma (HNSCC) is a leading cause of cancer-related deaths, with increasingly more cases arising due to high-risk human papillomavirus (HPV) infection. Cisplatin-based chemoradiotherapy is a standard-of-care for locally advanced head and neck cancer but is frequently ineffective. Research into enhancing radiation responses as a means of improving treatment outcomes represents a high priority. Here, we evaluated a CHK1 inhibitor (CCT244747) as a radiosensitiser and investigated whether a mechanistically rational triple combination of radiation/paclitaxel/CHK1 inhibitor delivered according to an optimized schedule would provide added benefit. CCT244747 abrogated radiation-induced G2 arrest in the p53-deficient HNSCC cell lines, HN4 and HN5, causing cells to enter mitosis with unrepaired DNA damage. The addition of paclitaxel further increased cell kill and significantly reduced tumor growth in an HN5 xenograft model. Importantly, a lower dose of paclitaxel could be used when CCT244747 was included, therefore potentially limiting toxicity. Triple therapy reduced the expression of several markers of radioresistance. Moreover, the more radioresistant HN5 cell line exhibited greater radiation-mediated CHK1 activation and was more sensitive to triple therapy than HN4 cells. We analyzed CHK1 expression in a panel of head and neck tumors and observed that primary tumors from HPV(+) patients, who went on to recur postradiotherapy, exhibited significantly stronger expression of total, and activated CHK1. CHK1 may serve as a biomarker for identifying tumors likely to recur and, therefore, patients who may benefit from concomitant treatment with a CHK1 inhibitor and paclitaxel during radiotherapy. Clinical translation of this strategy is under development. Mol Cancer Ther; 15(9); 2042-54. ©2016 AACR.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide [1], with smoking, alcohol consumption, and high-risk human papillomavirus (HPV) infection being the most common risk factors [2,3,4]
CHK1 inhibition radiosensitizes HN4 and HN5 cells To test the effect of inhibiting CHK1 on radiation-mediated G2 arrest, cells were treated with the CHK1 inhibitor, CCT244747, 1 hour before irradiation and collected at indicated time points
Radiation reduced the percentage of cells entering mitosis, suggesting that cells were arrested at the G2 phase of the cell cycle (Fig. 1A)
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading cancer worldwide [1], with smoking, alcohol consumption, and high-risk human papillomavirus (HPV) infection being the most common risk factors [2,3,4]. Radiotherapy is a standardof-care treatment for patients with HNSCC. Ionizing radiation induces a DNA damage response (DDR) that involves the cooperation of a complex network of proteins, which play roles in cellcycle checkpoints and DNA repair [5]. In normal cells, radiationinduced DNA damage predominantly induces a G1–S cell-cycle arrest as a result of p53 activation.
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