Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure

J. L. Dean, C. Thangavel, A. K. McClendon, C. A. Reed, E. S. Knudsen

Research output: Contribution to journalArticle

193 Scopus citations

Abstract

A hallmark of cancer is the deregulation of cell-cycle machinery, ultimately facilitating aberrant proliferation that fuels tumorigenesis and disease progression. Particularly, in breast cancers, cyclin D1 has a crucial role in the development of disease. Recently, a highly specific inhibitor of CDK4/6 activity (PD-0332991) has been developed that may have efficacy in the treatment of breast cancer. To interrogate the utility of PD-0332991 in treating breast cancers, therapeutic response was evaluated on a panel of breast cancer cell lines. These analyses showed that the chronic loss of Rb is specifically associated with evolution to a CDK4/6-independent state and, ultimately, resistance to PD-0332991. However, to interrogate the functional consequence of Rb directly, knockdown experiments were performed in models that represent immortalized mammary epithelia and multiple subtypes of breast cancer. These studies showed a highly specific role for Rb in mediating the response to CDK4/6 inhibition that was dependent on transcriptional repression manifest through E2F, and the ability to attenuate CDK2 activity. Acquired resistance to PD-03322991 was specifically associated with attenuation of CDK2 inhibitors, indicating that redundancy in CDK functions represents a determinant of therapeutic failure. Despite these caveats, in specific models, PD-0332991 was a particularly effective therapy, which induced Rb-dependent cytostasis. Combined, these findings indicate the critical importance of fully understanding cell-cycle regulatory pathways in directing the utilization of CDK inhibitors in the clinic.

Original languageEnglish (US)
Pages (from-to)4018-4032
Number of pages15
JournalOncogene
Volume29
Issue number28
DOIs
Publication statusPublished - Jul 2010

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Keywords

  • breast cancer
  • CDK4/6
  • cyclin D
  • E2F
  • PD-0332991
  • RB

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Dean, J. L., Thangavel, C., McClendon, A. K., Reed, C. A., & Knudsen, E. S. (2010). Therapeutic CDK4/6 inhibition in breast cancer: Key mechanisms of response and failure. Oncogene, 29(28), 4018-4032. https://doi.org/10.1038/onc.2010.154