CCR FOCUS From the Editor

How Do Cancer Cells Die? How do cancer cells die and how can we increase the fraction of cells that die after cancer treatment? This question has been a puzzle for almost 75 years, from the first i.v. administration in 1942 of a cancer chemotherapeutic to a patient, as described later by Fenn and Udelsman (1). We repeat the question when the tumor in one patient shrinks, while that in another patient grows. That cells would die after a chemotherapeutic interfered with DNA or with the cytoskeleton seems intuitive. But cancer cells also die from withdrawal of a hormone such as estrogen or androgen, blockade of a growth factor such as EGFR, loss of cellular attachment, interference with intracellular signaling, amino acid starvation, viral infection, and immune activation. Unequal triggers to be sure—some active, some passive—but, regardless of the trigger, the same outcome. Clearly, cell death is a complex event, and much less is known about how cells die than about the array of triggers. Several defined and distinct mechanisms are accepted: apoptosis, autophagy, and necroptosis. Work in this field is the subject of this section of CCR Focus with Guest Editor Anthony Letai, who has assembled a series of experts in the field. Two articles look at agents in the clinic that directly promote intrinsic apoptosis: Christopher Gibson and Matthew Davids on BCL-2 antagonists and Simone Fulda on SMAC mimetics. Eileen White and colleagues explain autophagy and its potential in the clinic. Finally, Luis Martínez-Lostao and colleagues ask what happens after immune activation—how do cancer cells die?

Publication of the first report of nitrogen mustard therapy for cancer (2). Copyright Ó 1946 American Medical Association. All rights reserved.

Successful drug therapy for a cancer requires distribution of the drug to the cancer cell, interaction or interference with the cellular target, and triggering and following the final common pathway to cell death. We know a lot about hitting the target, and we have many agents for that. At last, we may be able to treat the cell death pathways as therapeutic targets and leverage them in combination therapies. Susan E. Bates Deputy Editor, CCR Focus Columbia University Medical Center See all articles in this CCR Focus section, "Cell Death and Cancer Therapy."

References 1. Fenn JE, Udelsman R. First use of intravenous chemotherapy cancer treatment: rectifying the record. J Am Coll Surg 2011;212:413–7. 2. Goodman LS, Wintrobe MM, Dameshek W, Goodman MJ, Gilman A, McLennan MT. Nitrogen mustard therapy: use of methyl-bis(beta-chloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. JAMA 1946;132:126–32.

Published online November 13, 2015. doi: 10.1158/1078-0432.CCR-15-1203 Ó2015 American Association for Cancer Research.

5014 Clin Cancer Res; 21(22) November 15, 2015

Downloaded from clincancerres.aacrjournals.org on November 22, 2015. © 2015 American Association for Cancer Research.

How Do Cancer Cells Die? Susan E. Bates Clin Cancer Res 2015;21:5014.

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How Do Cancer Cells Die?

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