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

Oncogene volume 29, pages 4018–4032 (2010)Cite this article

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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.

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Authors and Affiliations

  1. Kimmel Cancer Center, Philadelphia, PA, USA

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

  2. Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA

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

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  1. J L Dean
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  2. C Thangavel
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Correspondence to E S Knudsen.

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Dean, J., Thangavel, C., McClendon, A. et al. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene 29, 4018–4032 (2010). https://doi.org/10.1038/onc.2010.154

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