Carfilzomib and ONX 0912 Inhibit Cell Survival and Tumor Growth of Head and Neck Cancer and Their Activities Are Enhanced by Suppression of Mcl-1 or Autophagy

• Published in: Clinical cancer research 2012-10, Vol.18 (20), p.5639-5649
• Main Authors: YAN ZANG, THOMAS, Sufi M, CHAN, Elena T, KIRK, Christopher J, FREILINO, Maria L, DELANCEY, Hannah M, GRANDIS, Jennifer R, CHANGYOU LI, JOHNSON, Daniel E
• Format: Article
• Language: English
• Subjects: Animals; Antinematodal Agents - administration & dosage; Antineoplastic agents; Apoptosis - drug effects; Autophagy - drug effects; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Survival - drug effects; Cell Transformation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - drug effects; Head and Neck Neoplasms - drug therapy; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - pathology; Humans; Medical sciences; Mice; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasms, Squamous Cell - drug therapy; Neoplasms, Squamous Cell - metabolism; Neoplasms, Squamous Cell - pathology; Oligopeptides - administration & dosage; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Proto-Oncogene Proteins c-bcl-2 - metabolism; Transplantation, Heterologous; Tumors; Unfolded Protein Response
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-12-1213

Carfilzomib is a selective, irreversible inhibitor of the chymotrypsin-like activity of the proteasome and is undergoing clinical evaluation in myeloma. ONX 0912 (oprozomib) is an orally bioavailable derivative. The activities of carfilzomib and ONX 0912 against solid tumor malignancies are less well understood. We investigated the impact and mechanisms of action of carfilzomib and ONX 0912 in preclinical models of head and neck squamous cell carcinoma (HNSCC). The effects of carfilzomib and ONX 0912 on HNSCC cell survival and xenograft tumor growth were evaluated. The impact and mechanisms of both agents on apoptosis and autophagy induction were also investigated. The contribution of the unfolded protein response (UPR) to autophagy induction and the role of autophagy in attenuating HNSCC cell death were determined. Carfilzomib and ONX 0912 potently induced apoptosis in HNSCC cell lines via upregulation of pro-apoptotic Bik. Upregulation of Mcl-1 by these agents served to dampen their efficacies. Carfilzomib and ONX 0912 also induced autophagy, mediated, in part, by activation of the UPR pathway involving upregulation of ATF4 transcription factor. Autophagy induction served a prosurvival role. Oral administration of ONX 0912 inhibited the growth of HNSCC xenograft tumors in a dose-dependent manner. These results show that carfilzomib and ONX 0912 are potently active against HNSCC cells, and the activities of these agents can be enhanced via suppression of Mcl-1 or inhibition of autophagy. Oral ONX 0912 exhibits in vivo activity against HNSCC tumors and may represent a useful therapeutic agent for this malignancy.