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A genomic approach to identify molecular pathways associated with chemotherapy resistance.

Publication ,  Journal Article
Riedel, RF; Porrello, A; Pontzer, E; Chenette, EJ; Hsu, DS; Balakumaran, B; Potti, A; Nevins, J; Febbo, PG
Published in: Mol Cancer Ther
October 2008

Resistance to chemotherapy in cancer is common. As gene expression profiling has been shown to anticipate chemotherapeutic resistance, we sought to identify cellular pathways associated with resistance to facilitate effective combination therapy. Gene set enrichment analysis was used to associate pathways with resistance in two data sets: the NCI-60 cancer cell lines deemed sensitive and resistant to specific chemotherapeutic agents (Adriamycin, cyclophosphamide, docetaxel, etoposide, 5-fluorouracil, paclitaxel, and topotecan) and a series of 40 lung cancer cell lines for which sensitivity to cisplatin and docetaxel was determined. Candidate pathways were further screened in silico using the Connectivity Map. The lead candidate pathway was functionally validated in vitro. Gene set enrichment analysis associated the matrix metalloproteinase, p53, methionine metabolism, and free pathways with cytotoxic resistance in the NCI-60 cell lines across multiple agents, but no gene set was common to all drugs. Analysis of the lung cancer cell lines identified the bcl-2 pathway to be associated with cisplatin resistance and the AKT pathway enriched in cisplatin- and docetaxel-resistant cell lines. Results from Connectivity Map supported an association between phosphatidylinositol 3-kinase/AKT and docetaxel resistance but did not support the association with cisplatin. Targeted inhibition of the phosphatidylinositol 3-kinase/AKT pathway with LY294002, in combination with docetaxel, resulted in a synergistic effect in previously docetaxel-resistant cell lines but not with cisplatin. These results support the use of a genomic approach to identify drug-specific targets associated with the development of chemotherapy resistance and underscore the importance of disease context in identifying these pathways.

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Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

October 2008

Volume

7

Issue

10

Start / End Page

3141 / 3149

Location

United States

Related Subject Headings

  • Taxoids
  • Sulfonamides
  • Proto-Oncogene Proteins c-akt
  • Phosphoinositide-3 Kinase Inhibitors
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Morpholines
  • Lung Neoplasms
  • Indoles
  • Humans
 

Citation

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Riedel, R. F., Porrello, A., Pontzer, E., Chenette, E. J., Hsu, D. S., Balakumaran, B., … Febbo, P. G. (2008). A genomic approach to identify molecular pathways associated with chemotherapy resistance. Mol Cancer Ther, 7(10), 3141–3149. https://doi.org/10.1158/1535-7163.MCT-08-0642
Riedel, Richard F., Alessandro Porrello, Emily Pontzer, Emily J. Chenette, David S. Hsu, Bala Balakumaran, Anil Potti, Joseph Nevins, and Phillip G. Febbo. “A genomic approach to identify molecular pathways associated with chemotherapy resistance.Mol Cancer Ther 7, no. 10 (October 2008): 3141–49. https://doi.org/10.1158/1535-7163.MCT-08-0642.
Riedel RF, Porrello A, Pontzer E, Chenette EJ, Hsu DS, Balakumaran B, et al. A genomic approach to identify molecular pathways associated with chemotherapy resistance. Mol Cancer Ther. 2008 Oct;7(10):3141–9.
Riedel, Richard F., et al. “A genomic approach to identify molecular pathways associated with chemotherapy resistance.Mol Cancer Ther, vol. 7, no. 10, Oct. 2008, pp. 3141–49. Pubmed, doi:10.1158/1535-7163.MCT-08-0642.
Riedel RF, Porrello A, Pontzer E, Chenette EJ, Hsu DS, Balakumaran B, Potti A, Nevins J, Febbo PG. A genomic approach to identify molecular pathways associated with chemotherapy resistance. Mol Cancer Ther. 2008 Oct;7(10):3141–3149.

Published In

Mol Cancer Ther

DOI

ISSN

1535-7163

Publication Date

October 2008

Volume

7

Issue

10

Start / End Page

3141 / 3149

Location

United States

Related Subject Headings

  • Taxoids
  • Sulfonamides
  • Proto-Oncogene Proteins c-akt
  • Phosphoinositide-3 Kinase Inhibitors
  • Paclitaxel
  • Oncology & Carcinogenesis
  • Morpholines
  • Lung Neoplasms
  • Indoles
  • Humans