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.

Abstract

PURPOSE:

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).

EXPERIMENTAL DESIGN:

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.

RESULTS:

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.

CONCLUSIONS:

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.

• Authors: Yan Zang, Sufi M Thomas, Elena T Chan, Christopher J Kirk, Maria L Freilino, Hannah M DeLancey, Jennifer R Grandis, Changyou Li, Daniel E Johnson
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 18 Issue 20 Pg. 5639-49 (Oct 15 2012) ISSN: 1557-3265 [Electronic] United States
• PMID: 22929803 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: ©2012 AACR

Chemical References

• Antinematodal Agents
• Mcl1 protein, mouse
• Myeloid Cell Leukemia Sequence 1 Protein
• ONX 0912
• Oligopeptides
• Proto-Oncogene Proteins c-bcl-2
• carfilzomib

Topics

• Animals
• Antinematodal Agents (administration & dosage)
• Apoptosis (drug effects)
• Autophagy (drug effects)
• 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, metabolism, pathology)
• Humans
• Mice
• Myeloid Cell Leukemia Sequence 1 Protein
• Neoplasms, Squamous Cell (drug therapy, metabolism, pathology)
• Oligopeptides (administration & dosage)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Transplantation, Heterologous
• Unfolded Protein Response