Combining Chk1/2 Inhibition with Cetuximab and Radiation Enhances In Vitro and In Vivo Cytotoxicity in Head and Neck Squamous Cell Carcinoma

Mol Cancer Ther. 2017 Apr;16(4):591-600. doi: 10.1158/1535-7163.MCT-16-0352. Epub 2017 Jan 30.

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 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.

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / pharmacology
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / therapy*
  • Carcinoma, Squamous Cell / virology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Proliferation / radiation effects
  • Cell Survival / drug effects
  • Cell Survival / radiation effects
  • Cetuximab / administration & dosage*
  • Cetuximab / pharmacology
  • Checkpoint Kinase 1 / antagonists & inhibitors
  • Checkpoint Kinase 2 / antagonists & inhibitors
  • Chemoradiotherapy / methods*
  • Combined Modality Therapy
  • DNA Damage
  • Drug Synergism
  • Gene Expression Regulation, Neoplastic / drug effects
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / therapy*
  • Head and Neck Neoplasms / virology
  • Humans
  • Mice
  • Pyrazines / administration & dosage*
  • Pyrazines / pharmacology
  • Pyrazoles / administration & dosage*
  • Pyrazoles / pharmacology
  • Squamous Cell Carcinoma of Head and Neck
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Pyrazines
  • Pyrazoles
  • prexasertib
  • Checkpoint Kinase 2
  • CHEK1 protein, human
  • CHEK2 protein, human
  • Checkpoint Kinase 1
  • Cetuximab

Associated data

  • ClinicalTrials.gov/NCT02555644