RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents

Kristy R. Stengel, Jeffry L. Dean, Sarah L. Seeley, Christopher N. Mayhew, Erik S. Knudsen

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The retinoblastoma tumor suppressor (RB) is frequently inactivated in human cancers and has been shown to modulate the anti-proliferative effects of DNA-damaging therapies. However, the impact of RB loss on response to disparately functioning cytotoxic agents as well as targeted therapies is poorly understood. Here 3T3-immortalized and Ras-transformed mouse adult fibroblasts (MAFs) containing conditional RB alleles were utilized to investigate the consequence of RB loss on cellular response to cytotoxic agents and therapies targeting the MEK and PI3K pathways. Using these models, we demonstrate that RB deficiency is associated with bypass of therapy-induced checkpoints in response to both cytotoxic and targeted treatments. Interestingly, while checkpoint bypass following treatment with cytotoxic therapy results in an agent specific increase in drug sensitivity, checkpoint bypass following treatment targeting MEK and PI3K function results in increased cellular proliferation. These results indicate that RB status differentially impacts therapeutic response and should be considered when evaluating the efficacy of molecularly targeted therapeutics.

Original languageEnglish (US)
Pages (from-to)1097-1105
Number of pages9
JournalCell Cycle
Volume7
Issue number8
StatePublished - Apr 15 2008

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Mitogen-Activated Protein Kinase Kinases
Cytotoxins
Phosphatidylinositol 3-Kinases
Fibroblasts
Tumors
DNA
Therapeutics
Pharmaceutical Preparations
Retinoblastoma
Genetic Therapy
Neoplasms
Alleles
Cell Proliferation

Keywords

  • Cell cycle checkpoints
  • Chemotherapeutics
  • Ras
  • Retinoblastoma tumor suppressor (RB)

ASJC Scopus subject areas

  • Cell Biology
  • Biochemistry
  • Molecular Biology

Cite this

Stengel, K. R., Dean, J. L., Seeley, S. L., Mayhew, C. N., & Knudsen, E. S. (2008). RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents. Cell Cycle, 7(8), 1097-1105.

RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents. / Stengel, Kristy R.; Dean, Jeffry L.; Seeley, Sarah L.; Mayhew, Christopher N.; Knudsen, Erik S.

In: Cell Cycle, Vol. 7, No. 8, 15.04.2008, p. 1097-1105.

Research output: Contribution to journalArticle

Stengel, KR, Dean, JL, Seeley, SL, Mayhew, CN & Knudsen, ES 2008, 'RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents', Cell Cycle, vol. 7, no. 8, pp. 1097-1105.
Stengel KR, Dean JL, Seeley SL, Mayhew CN, Knudsen ES. RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents. Cell Cycle. 2008 Apr 15;7(8):1097-1105.
Stengel, Kristy R. ; Dean, Jeffry L. ; Seeley, Sarah L. ; Mayhew, Christopher N. ; Knudsen, Erik S. / RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents. In: Cell Cycle. 2008 ; Vol. 7, No. 8. pp. 1097-1105.
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