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Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer.

Publication ,  Journal Article
Oliver, TG; Mercer, KL; Sayles, LC; Burke, JR; Mendus, D; Lovejoy, KS; Cheng, M-H; Subramanian, A; Mu, D; Powers, S; Crowley, D; Bronson, RT ...
Published in: Genes Dev
April 15, 2010

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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Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

April 15, 2010

Volume

24

Issue

8

Start / End Page

837 / 852

Location

United States

Related Subject Headings

  • Oligonucleotide Array Sequence Analysis
  • Mice
  • Lung Neoplasms
  • Humans
  • Gene Expression Profiling
  • Drug Resistance, Neoplasm
  • Disease Models, Animal
  • Developmental Biology
  • Death Domain Receptor Signaling Adaptor Proteins
  • DNA Repair
 

Citation

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Oliver, T. G., Mercer, K. L., Sayles, L. C., Burke, J. R., Mendus, D., Lovejoy, K. S., … Sweet-Cordero, E. A. (2010). Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev, 24(8), 837–852. https://doi.org/10.1101/gad.1897010
Oliver, Trudy G., Kim L. Mercer, Leanne C. Sayles, James R. Burke, Diana Mendus, Katherine S. Lovejoy, Mei-Hsin Cheng, et al. “Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer.Genes Dev 24, no. 8 (April 15, 2010): 837–52. https://doi.org/10.1101/gad.1897010.
Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, et al. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev. 2010 Apr 15;24(8):837–52.
Oliver, Trudy G., et al. “Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer.Genes Dev, vol. 24, no. 8, Apr. 2010, pp. 837–52. Pubmed, doi:10.1101/gad.1897010.
Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, Cheng M-H, Subramanian A, Mu D, Powers S, Crowley D, Bronson RT, Whittaker CA, Bhutkar A, Lippard SJ, Golub T, Thomale J, Jacks T, Sweet-Cordero EA. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev. 2010 Apr 15;24(8):837–852.

Published In

Genes Dev

DOI

EISSN

1549-5477

Publication Date

April 15, 2010

Volume

24

Issue

8

Start / End Page

837 / 852

Location

United States

Related Subject Headings

  • Oligonucleotide Array Sequence Analysis
  • Mice
  • Lung Neoplasms
  • Humans
  • Gene Expression Profiling
  • Drug Resistance, Neoplasm
  • Disease Models, Animal
  • Developmental Biology
  • Death Domain Receptor Signaling Adaptor Proteins
  • DNA Repair