Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer
- Trudy G. Oliver1,2,
- Kim L. Mercer1,2,3,
- Leanne C. Sayles4,
- James R. Burke1,2,3,
- Diana Mendus5,
- Katherine S. Lovejoy1,6,
- Mei-Hsin Cheng2,
- Aravind Subramanian7,
- David Mu8,
- Scott Powers9,
- Denise Crowley1,2,3,
- Roderick T. Bronson10,
- Charles A. Whittaker1,
- Arjun Bhutkar1,
- Stephen J. Lippard1,6,
- Todd Golub3,7,11,
- Juergen Thomale5,
- Tyler Jacks1,2,3,13 and
- E. Alejandro Sweet-Cordero4,12
- 1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 2Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 3Howard Hughes Medical Institute, Chevy Chase, Maryland 20185, USA;
- 4Cancer Biology Program, Stanford University Medical School, Stanford, California 94305, USA;
- 5Institute for Cell Biology (Cancer Research), University of Duisburg-Essen Medical School, Essen 45122, Germany;
- 6Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 7Eli and Lily Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA;
- 8Department of Pathology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA;
- 9Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11797, USA;
- 10Department of Pathology, Tufts University School of Medicine and Veterinary Medicine, Boston, Massachusetts 02155, USA;
- 11Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA;
- 12Division of Pediatric Hematology/Oncology, Department of Pediatrics, Stanford University Medical School, Stanford, California 94305, USA
Abstract
Chemotherapy resistance is a major obstacle in cancer treatment, yet the mechanisms of response to specific therapies have been largely unexplored in vivo. Employing genetic, genomic, and imaging approaches, we examined the dynamics of response to a mainstay chemotherapeutic, cisplatin, in multiple mouse models of human non-small-cell lung cancer (NSCLC). We show that lung tumors initially respond to cisplatin by sensing DNA damage, undergoing cell cycle arrest, and inducing apoptosis—leading to a significant reduction in tumor burden. Importantly, we demonstrate that this response does not depend on the tumor suppressor p53 or its transcriptional target, p21. Prolonged cisplatin treatment promotes the emergence of resistant tumors with enhanced repair capacity that are cross-resistant to platinum analogs, exhibit advanced histopathology, and possess an increased frequency of genomic alterations. Cisplatin-resistant tumors express elevated levels of multiple DNA damage repair and cell cycle arrest-related genes, including p53-inducible protein with a death domain (Pidd). We demonstrate a novel role for PIDD as a regulator of chemotherapy response in human lung tumor cells.
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Footnotes
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↵13 Corresponding author.
E-MAIL tjacks{at}mit.edu; FAX (617) 253-9863.
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Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1897010.
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Supplemental material is available at http://www.genesdev.org.
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- Received December 15, 2009.
- Accepted March 1, 2010.
- Copyright © 2010 by Cold Spring Harbor Laboratory Press