Abstract 2439: Obatoclax (GX15-070) potently induces apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines and enhances the activity of EGFR inhibitors.

Abstract

Abstract HNSCC represents 90% of head and neck tumors. More than half of HNSCC patients are initially treated with curative intent, but will relapse over the course of their disease and have poor prognosis with a median survival of 6-9 months. Novel therapeutic approaches are in desperate need for this patient population. The antiapoptotic BCL-2 family proteins like BCL-2, BCL-XL, and MCL-1 are involved in oncogenesis and chemoresistance and are overexpressed in HNSCC. Obatoclax is a small-molecule antagonist of the BH3-binding groove of the prosurvival (or anti-apoptotic) members of the BCL-2 family of proteins. It is the only compound among the current BCL-2 inhibitors in clinical trials that is capable of inhibiting MCL-1, in addition to BCL-2 and BCL-XL. We determined the activity of obatoclax in 4 HNSCC cell lines (UMSCC-1, Cal-33, 1483, UMSCC-22A). Cell viability was determined by MTT assay, and apoptosis by Annexin-V binding, FACS analysis and immunoblotting. All four HNSCC cell lines were highly sensitive to single agent obatoclax with IC50’s ranging from 50-300 nM. Obatoclax induced apoptosis in all four HNSCC cell lines as evidenced by increased Annexin-V binding at 48 hours from 10% in vehicle treated cells to 30-60% and through cleavage of caspase 3 and PARP. Interestingly, obatoclax enhanced the activity of the two small tyrosine kinase inhibitors of EGFR (erlotinib and gefitinib). We are the first to show the activity of obatoclax in HNSCC alone and in combination with EGFR inhibitors. In vivo study of obatoclax using human HNSCC xenograft tumors is currently underway. This preclinical study suggests that obatoclax might have a therapeutic role in HNSCC either alone or in combination with EGFR inhibitors. Citation Format: Victor Y. Yazbeck, Kathleen Dorritie, Changyou Li, Jennifer Grandis, Yan Zang, Daniel E. Johnson. Obatoclax (GX15-070) potently induces apoptosis in head and neck squamous cell carcinoma (HNSCC) cell lines and enhances the activity of EGFR inhibitors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2439. doi:10.1158/1538-7445.AM2013-2439