Oliver, T. G., Mercer, K. L., Sayles, L. C., Burke, J. R., Mendus, D., Lovejoy, K. S., Cheng, M. H., Subramanian, A., Mu, D., Powers, S., Crowley, D., Bronson, R. T., Whittaker, C. A., Bhutkar, A., Lippard, S. J., Golub, T., Thomale, J., Jacks, T., Sweet-Cordero, E. A. (April 2010) Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes & Development, 24 (8). pp. 837-852. ISSN 0890-9369
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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.
| Item Type: | Paper |
|---|---|
| Uncontrolled Keywords: | Mouse models cisplatin Kras p53 chemotherapy resistance lung cancer NON-SMALL-CELL PLATINUM-BASED CHEMOTHERAPY NUCLEOTIDE EXCISION-REPAIR INDUCED DNA-DAMAGE ADJUVANT CHEMOTHERAPY TRANSPORTER CTR1 GENOTOXIC STRESS TYROSINE KINASE GENE-EXPRESSION P53 MUTATIONS |
| Subjects: | diseases & disorders > cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > DNA, RNA structure, function, modification > transcription diseases & disorders > cancer > drugs and therapies > cisplatin diseases & disorders > cancer > cancer types > lung cancer bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase > tyrosine kinase |
| CSHL Authors: | |
| Communities: | CSHL labs > Powers lab |
| Depositing User: | CSHL Librarian |
| Date: | April 2010 |
| Date Deposited: | 05 Oct 2011 14:20 |
| Last Modified: | 24 Feb 2017 20:58 |
| PMCID: | PMC2854397 |
| Related URLs: | |
| URI: | https://repository.cshl.edu/id/eprint/15499 |
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