title: The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation.
abstract: 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.
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology.
authors.forename: Debasish
authors.initials: D
authors.lastname: Raha
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Wilson
authors.affiliation: Translational Oncology, and.
authors.forename: Jing
authors.initials: J
authors.lastname: Peng
authors.affiliation: Translational Oncology, and.
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.affiliation: Bioinformatics, Genentech, Inc., South San Francisco, California.
authors.forename: Peng
authors.initials: P
authors.lastname: Yue
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology.
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology.
authors.forename: Catherine
authors.initials: C
authors.lastname: Wilson
authors.affiliation: Translational Oncology, and.
authors.forename: Mark
authors.initials: M
authors.lastname: Merchant
authors.affiliation: Authors' Affiliations: Departments of Discovery Oncology, settleman.jeffrey@gene.com.
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D000077547:Crizotinib; D004249:DNA Damage; D004221:Disulfiram / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000201:enzymology*; D018384:Oxidative Stress; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D011799:Quinazolines; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D000077547:Crizotinib; D000069347:Erlotinib Hydrochloride; D000444:Aldehyde Dehydrogenase; D066246:ErbB Receptors; D004221:Disulfiram