Abstract
Treatment of advanced head and neck squamous cell carcinoma (HNSCC) is plagued by low survival and high recurrence rates, despite multimodal therapies. Presently, cisplatin or cetuximab is used in combination with radiotherapy which has resulted in minor survival benefits but increased severe toxicities relative to RT alone. This underscores the urgent need for improved tumor-specific radiosensitizers for better control with lower toxicities. In a small molecule screen targeting kinases, performed on three HNSCC cell lines, we identified GSK635416A as a novel radiosensitizer. The extent of radiosensitization by GSK635416A outperformed the radiosensitization observed with cisplatin and cetuximab in our models, while exhibiting virtually no cytotoxicity in the absence of radiation and in normal fibroblast cells. Radiation induced phosphorylation of ATM was inhibited by GSK635416A. GSK63541A increased DNA double strand breaks after radiation and GSK63541A mediated radiosensitization was lacking in ATM-mutated cells thereby further supporting the ATM inhibiting properties of GSK63541A. As a novel ATM inhibitor with highly selective radiosensitizing activity, GSK635416A holds promise as a lead in the development of drugs active in potentiating radiotherapy for HNSCC and other cancer types.
Highlights
Of the estimated 686,000 new head and neck cancer cases per year worldwide [1], seventy percent of head and neck squamous cell carcinoma (HNSCC) patients enter the clinic with advanced stage disease and exhibit an overall 5-year survival rate of only 35–60% [2,3,4]
While CCRT is presently favoured over cetuximab-RT in routine care [10], it is clear that many HNSCC patients are not receiving benefits from the currently available treatments, highlighting an urgent need for alternatives
Plating efficiencies (PE) in the colony forming assay (CFA) were not different and did not decrease under 2 μM of GSK635416A treatment compared to vehicle treated controls, thereby confirming a lack of clonogenic cell death at this drug concentration without ionizing radiation (IR) (Supplementary Figure 1A)
Summary
Of the estimated 686,000 new head and neck cancer cases per year worldwide [1], seventy percent of HNSCC patients enter the clinic with advanced stage disease and exhibit an overall 5-year survival rate of only 35–60% [2,3,4]. In an effort to improve cure rates and functional outcomes of locally advanced HNSCC, high-dose cisplatin chemotherapy has been integrated into the RT treatment regimens (CCRT) since the early 1980’s [5]. Meta-analysis of randomized trials has indicated only a moderate absolute overall survival benefit of 6.5% at 5 years for HNSCC patients upon addition of cisplatin to locoregional RT [6]. Www.impactjournals.com/oncotarget in addition to the high local recurrence rate in more than 50% of patients, CCRT is accompanied with a substantial increase in severe adverse events, including mucositis, dysphagia, nephrotoxicity and hematologic toxicity [7]. Only one trial reported efficacy of cetuximabRT in HNSCC [8], while a recent phase 2 randomized trial, comparing RT with concomitant cisplatin versus cetuximab, showed that cetuximab increased acute toxicity rates without a corresponding clinical benefit [9]. Pre-clinical studies show efficient sensitization to RT in various tumor types [11,12,13,14]
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