The Cancer Stem Cell Marker Aldehyde Dehydrogenase Is Required to Maintain a Drug-Tolerant Tumor Cell Subpopulation

• Published in: Cancer research (Chicago, Ill.) Vol. 74; no. 13; pp. 3579 - 3590
• Main Authors: RAHA, Debasish, WILSON, Timothy R, JING PENG, PETERSON, David, PENG YUE, EVANGELISTA, Marie, WILSON, Catherine, MERCHANT, Mark, SETTLEMAN, Jeff
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.07.2014
• Subjects: Aldehyde Dehydrogenase - antagonists & inhibitors; Aldehyde Dehydrogenase - metabolism; Animals; Antineoplastic agents; Apoptosis - drug effects; Biological and medical sciences; Cell Line, Tumor; Cell Survival; Disulfiram - pharmacology; DNA Damage; Drug Resistance, Neoplasm; Erlotinib Hydrochloride; Humans; Medical sciences; Mice; Mice, Nude; Neoplastic Stem Cells - drug effects; Neoplastic Stem Cells - enzymology; Oxidative Stress; Pharmacology. Drug treatments; Protein Kinase Inhibitors - pharmacology; Pyrazoles - pharmacology; Pyridines - pharmacology; Quinazolines - pharmacology; Reactive Oxygen Species - metabolism; Receptor, Epidermal Growth Factor - antagonists & inhibitors; RNA Interference; RNA, Small Interfering; Tumors; Xenograft Model Antitumor Assays; Drug; Enzyme; Aldehyde dehydrogenase (NAD; Stem cell; Biological marker; ); Oxidoreductases; Cell subpopulation; Tumor cell
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-13-3456

Selective kinase inhibitors have emerged as an important class of cancer therapeutics, and several such drugs are now routinely used to treat advanced-stage disease. However, their clinical benefit is typically short-lived because of the relatively rapid acquisition of drug resistance following treatment response. Accumulating preclinical and clinical data point to a role for a heterogeneous response to treatment within a subpopulation of tumor cells that are intrinsically drug-resistant, such as cancer stem cells. We have previously described an epigenetically determined reversibly drug-tolerant subpopulation of cancer cells that share some properties with cancer stem cells. Here, we define a requirement for the previously established cancer stem cell marker ALDH (aldehyde dehydrogenase) in the maintenance of this drug-tolerant subpopulation. We find that ALDH protects the drug-tolerant subpopulation from the potentially toxic effects of elevated levels of reactive oxygen species (ROS) in these cells, and pharmacologic disruption of ALDH activity leads to accumulation of ROS to toxic levels, consequent DNA damage, and apoptosis specifically within the drug-tolerant subpopulation. Combining ALDH inhibition with other kinase-directed treatments delayed treatment relapse in vitro and in vivo, revealing a novel combination treatment strategy for cancers that might otherwise rapidly relapse following single-agent therapy.