MCL1 inhibition enhances the efficacy of docetaxel against airway-derived squamous cell carcinoma cells.

Abstract

MCL1 is an anti-apoptotic BCL2 family member that is often overexpressed in various malignant tumors. However, few reports have described the role of MCL1 in squamous cell carcinoma (SqCC) derived from airways including the lung. In this study, we examined whether MCL1 could be a novel druggable target for airway-derived SqCC, for which effective molecular targeted drugs are unavailable. We searched the Kaplan-Meier Plotter database and found that high MCL1 mRNA expression was significantly associated with shorter survival in patients with lower airway (lung) or upper airway (head and neck) derived SqCC. We also explored the Expression Atlas database and learned that authentic lung SqCC cell lines expressing both TP63 and KRT5 mRNA were extremely sparse among the publicly available "lung SqCC cell lines", with an exception being HARA cells. HARA cells were highly dependent on MCL1 for survival, and MCL1-depleted cells were not able to grow, and even declined in number, upon docetaxel (DTX) exposure in vitro and in vivo. Similar in vitro experimental findings, including those in a 3D culture model, were also obtained using Detroit 562 pharyngeal SqCC cells. These findings suggested that combined treatment with MCL1 silencing plus DTX appears highly effective against airway-derived SqCC.

• Authors: Yuji Sakuma, Sachie Hirai, Toshiyuki Sumi, Makoto Tada, Takashi Kojima, Toshiro Niki, Miki Yamaguchi
• Journal: Experimental cell research (Exp Cell Res) Vol. 406 Issue 2 Pg. 112763 (09 15 2021) ISSN: 1090-2422 [Electronic] United States
• PMID: 34358524 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

Chemical References

• Antineoplastic Agents
• MCL1 protein, human
• Myeloid Cell Leukemia Sequence 1 Protein
• Docetaxel

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis
• Carcinoma, Squamous Cell (drug therapy, metabolism, pathology)
• Cell Proliferation
• Docetaxel (pharmacology)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, metabolism, pathology)
• Mice
• Mice, Nude
• Myeloid Cell Leukemia Sequence 1 Protein (antagonists & inhibitors)
• Prognosis
• Survival Rate
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays