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

73 Scopus citations

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

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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