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

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)1095-1103
Number of pages9
JournalCell cycle (Georgetown, Tex.)
Volume7
Issue number8
StatePublished - Apr 2008

Fingerprint

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

ASJC Scopus subject areas

  • Medicine(all)

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 (Georgetown, Tex.), 7(8), 1095-1103.

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 (Georgetown, Tex.), Vol. 7, No. 8, 04.2008, p. 1095-1103.

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 (Georgetown, Tex.), vol. 7, no. 8, pp. 1095-1103.
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 (Georgetown, Tex.). 2008 ; Vol. 7, No. 8. pp. 1095-1103.
@article{7c0ac54f3ed047f1b41b82113e6882b0,
title = "RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents.",
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.",
author = "Stengel, {Kristy R.} and Dean, {Jeffry L.} and Seeley, {Sarah L.} and Mayhew, {Christopher N.} and Knudsen, {Erik S.}",
year = "2008",
month = "4",
language = "English (US)",
volume = "7",
pages = "1095--1103",
journal = "Cell Cycle",
issn = "1538-4101",
publisher = "Landes Bioscience",
number = "8",

}

TY - JOUR

T1 - RB status governs differential sensitivity to cytotoxic and molecularly-targeted therapeutic agents.

AU - Stengel, Kristy R.

AU - Dean, Jeffry L.

AU - Seeley, Sarah L.

AU - Mayhew, Christopher N.

AU - Knudsen, Erik S.

PY - 2008/4

Y1 - 2008/4

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=50649116451&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50649116451&partnerID=8YFLogxK

M3 - Article

C2 - 18414045

VL - 7

SP - 1095

EP - 1103

JO - Cell Cycle

JF - Cell Cycle

SN - 1538-4101

IS - 8

ER -