Modification of the DNA damage response by therapeutic CDK4/6 inhibition

Jeffry L. Dean, A. Kathleen McClendon, Erik S. Knudsen

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

The RB/E2F axis represents a critical node of cell signaling that integrates a diverse array of signaling pathways. Recent evidence has suggested a role for E2F-mediated gene transcription inDNAdamage response and repair, as well as apoptosis signaling. Herein, we investigated how repression of E2F activity via CDK4/6 inhibition and RB activation impacts the response of triple negative breast cancer (TNBC) to frequently used therapeutic agents. In combination with taxanes and anthracyclines CDK4/6 inhibition and consequent cell cycle arrest prevented the induction of DNA damage and associated cell death in an RB-dependent manner; thereby demonstrating antagonism between the cytostatic influence of the CDK-inhibitor and cytotoxic agents. As many of these effects were secondary to cell cycle arrest, γ-irradiation (IR) was utilized to examine effects of CDK4/6 inhibition on direct DNA damage. Although E2F controls a number of genes involved in DNA repair (e.g. Rad51), CDK4/6 inhibition did not alter the overall rate of DNA repair, rather it significantly shifted the burden of this repair from homologous recombination (HR) to non-homologous end joining (NHEJ). Together, these data indicate that CDK4/6 inhibition can antagonize cytotoxic therapeutic strategies and increases utilization of error-prone DNA repair mechanisms that could contribute to disease progression.

Original languageEnglish (US)
Pages (from-to)29075-29087
Number of pages13
JournalJournal of Biological Chemistry
Volume287
Issue number34
DOIs
StatePublished - Aug 17 2012

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DNA Repair
DNA Damage
Repair
Cell Cycle Checkpoints
DNA
Triple Negative Breast Neoplasms
Recombinational DNA Repair
Taxoids
Anthracyclines
Cytotoxins
Cytostatic Agents
Genes
Cells
Disease Progression
Cell signaling
Cell Death
Therapeutics
Apoptosis
Cell death
Transcription

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

Modification of the DNA damage response by therapeutic CDK4/6 inhibition. / Dean, Jeffry L.; McClendon, A. Kathleen; Knudsen, Erik S.

In: Journal of Biological Chemistry, Vol. 287, No. 34, 17.08.2012, p. 29075-29087.

Research output: Contribution to journalArticle

Dean, Jeffry L. ; McClendon, A. Kathleen ; Knudsen, Erik S. / Modification of the DNA damage response by therapeutic CDK4/6 inhibition. In: Journal of Biological Chemistry. 2012 ; Vol. 287, No. 34. pp. 29075-29087.
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