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|Ref Type||Journal Article|
|Authors||Zeng L, Beggs RR, Cooper TS, Weaver AN, Yang ES|
|Title||Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma.|
|Journal||Molecular cancer therapeutics|
|Abstract Text||EGFR inhibition and radiotherapy are potent inducers of DNA damage. Checkpoint kinases 1 and 2 (Chk1/2) are critical regulators of the DNA-damage response, controlling cell-cycle checkpoints that may permit recovery from therapy-associated genomic stress. We hypothesized that Chk1/2 inhibition (CHKi) with prexasertib may enhance cytotoxicity from EGFR inhibition plus radiotherapy in head and neck squamous cell carcinoma (HNSCC). In this study, we found that the addition of CHKi to the EGFR inhibitor cetuximab with and without radiotherapy significantly decreased cell proliferation and survival fraction in human papillomavirus virus (HPV)-positive and HPV-negative HNSCC cell lines. Reduced proliferation was accompanied by decreased checkpoint activation, induced S-phase accumulation, persistent DNA damage, and increased caspase cleavage and apoptosis. Importantly, a significant tumor growth delay was observed in vivo in both HPV-positive and HPV-negative cell line xenografts receiving triple combination therapy with CHKi, cetuximab, and radiotherapy without a concomitant increase in toxicity as assessed by mouse body weight. Taken together, the combination of CHKi with cetuximab plus irradiation displayed significant antitumor effects in HNSCCs both in vitro and in vivo, suggesting that this combination therapy may increase clinical benefit. A clinical trial to test this treatment for patients with head and neck cancer is currently ongoing (NCT02555644). Mol Cancer Ther; 16(4); 591-600. ©2017 AACR.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|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|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Prexasertib||Preclinical - Cell culture||Actionable||In a preclinical study, head and neck squamous cell carcinoma cell lines, either human papilloma virus positive or negative, demonstrated decreased cell proliferation in culture when treated with Prexasertib (LY2606368) (PMID: 28138028).||28138028|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Cetuximab + Prexasertib||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of Erlotinib (cetuximab) and Prexasertib (LY2606368 resulted in greater decreased cell proliferation in head and neck squamous cell carcinoma cells in culture compared to either agent alone (PMID: 28138028).||28138028|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Cetuximab||Preclinical - Cell culture||Actionable||In a preclinical study, head and neck squamous cell carcinoma cell lines, either human papilloma virus positive or negative, demonstrated decreased cell proliferation in culture when treated with Erlotinib (cetuximab) (PMID: 28138028).||28138028|
|Unknown unknown||head and neck squamous cell carcinoma||not applicable||Cetuximab + Prexasertib + Radiotherapy||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of Prexasertib (LY2606368), Erlotinib (cetuximab), and radiotherapy resulted in greater decreased cell proliferation, inhibition of cell growth, and apoptotic activity in culture compared to either agent alone, and suppressed tumor growth in cell line xenograft models (PMID: 28138028).||28138028|