Retinoblastoma deficiency increases chemosensitivity in lung cancer

William A. Zagorski, Erik S. Knudsen, Michael F. Reed

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

The retinoblastoma (RB) tumor suppressor is mutated or functionally inactivated in the majority of human malignancies, and p16INK4a- cyclin D1-cyclin-dependent kinase 4-RB pathway aberrations are present in nearly all cases of non-small cell lung cancer (NSCLC). Here, the distinct role of RB loss in tumorigenic proliferation and sensitivity to chemotherapeutics was determined in NSCLC cells. Attenuation of RB led to a proliferative advantage in vitro and aggressive tumorigenic growth in xenograft models. Clinically, such aggressive disease is treated with genotoxic and cytotoxic chemotherapeutic agents. In vitro analysis showed that RB deficiency resulted in bypass of the checkpoint response to multiple chemotherapeutic challenges concomitant with an elevated apoptotic response. Correspondingly, RB deficiency in xenograft models led to increased chemosensitivity. However, this response was transient, and a durable response was dependent on prolonged chemotherapeutic administration. Together, these findings show that although RB deficiency enhances sensitivity to chemotherapeutic challenge, efficient and sustainable response is highly dependent on the specific therapeutic regimen, in addition to the molecular environment.

Original languageEnglish (US)
Pages (from-to)8264-8273
Number of pages10
JournalCancer Research
Volume67
Issue number17
DOIs
StatePublished - Sep 1 2007

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Retinoblastoma
Lung Neoplasms
Heterografts
Non-Small Cell Lung Carcinoma
Cyclin-Dependent Kinase 4
Cyclin D1
Cytotoxins
Neoplasms
Growth

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Retinoblastoma deficiency increases chemosensitivity in lung cancer. / Zagorski, William A.; Knudsen, Erik S.; Reed, Michael F.

In: Cancer Research, Vol. 67, No. 17, 01.09.2007, p. 8264-8273.

Research output: Contribution to journalArticle

Zagorski, William A. ; Knudsen, Erik S. ; Reed, Michael F. / Retinoblastoma deficiency increases chemosensitivity in lung cancer. In: Cancer Research. 2007 ; Vol. 67, No. 17. pp. 8264-8273.
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