Reference Detail

Ref Type

Journal Article

PMID

(27422809)

Authors

Barker HE, Patel R, McLaughlin M, Schick U, Zaidi S, Nutting CM, Newbold KL, Bhide S, Harrington KJ

Title

CHK1 Inhibition Radiosensitizes Head and Neck Cancers to Paclitaxel-Based Chemoradiotherapy.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	9	2016 Sep	2042-54	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials
CCT244747	CCT244747	0	0

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description
CCT244747		SYN-1216	CHK1 Inhibitor 17	CCT244747 inhibits CHK1, potentially resulting in increased tumor cell death and increased sensitivity to other antitumor agents (PMID: 22929806, PMID: 27422809, PMID: 28131548).

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
CHEK1 positive	head and neck squamous cell carcinoma	sensitive	CCT244747 + Paclitaxel + Radiotherapy	Preclinical - Cell line xenograft	Actionable	In a preclinical study, CCT244747, Taxol (paclitaxel), and radiation triple therapy synergistically inhibited Chek1 activation, and resulted in growth inhibition of head and neck squamous cell carcinoma cell lines in culture and in cell line xenograft models (PMID: 27422809).	27422809
CHEK1 positive	head and neck squamous cell carcinoma	sensitive	CCT244747 + Radiotherapy	Preclinical - Cell culture	Actionable	In a preclinical study, CCT244747 inhibited Chek1 activation, resulted in sensitizing head and neck squamous cell carcinoma cell lines to radiation treatment in culture (PMID: 27422809).	27422809