title: Combining Chk1/2 Inhibition with Cetuximab and Radiation EnhancesIn VitroandIn VivoCytotoxicity in Head and Neck Squamous Cell Carcinoma.
abstract: 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 observedin vivoin 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 bothin vitroandin 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.
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Ling
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Reena R
authors.initials: RR
authors.lastname: Beggs
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Tiffiny S
authors.initials: TS
authors.lastname: Cooper
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Alice N
authors.initials: AN
authors.lastname: Weaver
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama. eyang@uab.edu.|Department of Pharmacology and Toxiology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.|Department of Cell, Developmental, and Integrative Biology, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.|Comprehensive Cancer Center, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama.
authors.forename: Eddy S
authors.initials: ES
authors.lastname: Yang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000628:therapy* / Q000821:virology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab / Q000008:administration & dosage* / Q000494:pharmacology; D000071877:Checkpoint Kinase 1 / Q000037:antagonists & inhibitors; D064447:Checkpoint Kinase 2 / Q000037:antagonists & inhibitors; D059248:Chemoradiotherapy / Q000379:methods*; D003131:Combined Modality Therapy; D004249:DNA Damage; D004357:Drug Synergism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000628:therapy* / Q000821:virology; D006801:Humans; D051379:Mice; D011719:Pyrazines / Q000008:administration & dosage* / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage* / Q000494:pharmacology; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D011719:Pyrazines; D011720:Pyrazoles; C000608121:prexasertib; D064447:Checkpoint Kinase 2; C000605867:CHEK1 protein, human; C578634:CHEK2 protein, human; D000071877:Checkpoint Kinase 1; D000068818:Cetuximab