Wee-1 Kinase Inhibition Sensitizes High-Risk HPV+ HNSCC to Apoptosis Accompanied by Downregulation of MCl-1 and XIAP Antiapoptotic Proteins.

Abstract

PURPOSE:

Although the majority of patients with HPV(+) oropharyngeal cancers have a favorable prognosis, there are some patients with tumors that are resistant to aggressive chemoradiotherapy with unusual patterns of locoregional and systemic recurrences. Therefore, more effective therapies are needed. In this study, we investigated the chemosensitizing efficacy of the selective Wee-1 kinase inhibitor, AZD-1775, in HPV(+) head and neck squamous cell carcinoma (HNSCC).

EXPERIMENTAL DESIGN:

Clonogenic survival assays and an orthotopic mouse model of HPV(+) oral cancer were used to examine the in vitro and in vivo sensitivity of HPV(+) HNSCC cell lines to AZD-1775 in combination with cisplatin, respectively. Cell-cycle analysis, DNA damage (γH2AX), homologous recombination (HR), and apoptosis were examined to dissect molecular mechanisms.

RESULTS:

We found that AZD-1775 displays single-agent activity and enhances the response of HPV(+) HNSCC cells to cisplatin both in vitro and in vivo. The sensitivity of the HPV(+) HNSCC cells to AZD-1775 alone or in combination with cisplatin was associated with G2 checkpoint abrogation, persistent DNA damage, and apoptosis induction. This finding of AZD-1775 increasing the sensitivity of HPV(+) HNSCC cells to cisplatin through apoptosis was not seen previously in the HPV(-) HNSCC cancer cells and is accompanied by a decreased expression of the antiapoptotic proteins, MCl-1and XIAP, which appear to be cleaved following AZD-1775 treatment.

CONCLUSIONS:

AZD-1775 selectively sensitizes HPV(+) HNSCC cells and orthotopic oral xenografts to cisplatin through apoptosis and support the clinical investigation of AZD-1775 in combination with cisplatin particularly in patients with advanced and recurrent metastatic HPV(+) HNSCC tumors.

• Authors: Noriaki Tanaka, Ameeta A Patel, Jiping Wang, Mitchell J Frederick, Nene N Kalu, Mei Zhao, Alison L Fitzgerald, Tong-xin Xie, Natalie L Silver, Carlos Caulin, Ge Zhou, Heath D Skinner, Faye M Johnson, Jeffrey N Myers, Abdullah A Osman
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 21 Pg. 4831-44 (Nov 01 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 26124202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents
• Cell Cycle Proteins
• Myeloid Cell Leukemia Sequence 1 Protein
• Nuclear Proteins
• Protein Kinase Inhibitors
• Pyrazoles
• Pyrimidines
• Pyrimidinones
• X-Linked Inhibitor of Apoptosis Protein
• Protein-Tyrosine Kinases
• WEE1 protein, human
• Caspases
• adavosertib
• Cisplatin

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Carcinoma, Squamous Cell (etiology, metabolism)
• Caspases (metabolism)
• Cell Cycle Proteins (antagonists & inhibitors)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology)
• Disease Models, Animal
• Drug Resistance, Neoplasm (genetics)
• Drug Synergism
• G2 Phase Cell Cycle Checkpoints (drug effects)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knockdown Techniques
• Genes, p53
• Head and Neck Neoplasms (etiology, metabolism)
• Humans
• Inhibitory Concentration 50
• Male
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein (genetics, metabolism)
• Nuclear Proteins (antagonists & inhibitors)
• Papillomavirus Infections (complications, virology)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (antagonists & inhibitors)
• Pyrazoles (pharmacology)
• Pyrimidines (pharmacology)
• Pyrimidinones
• Squamous Cell Carcinoma of Head and Neck
• Tumor Burden (drug effects)
• X-Linked Inhibitor of Apoptosis Protein (genetics, metabolism)
• Xenograft Model Antitumor Assays