Chk’ing p53-deficient breast cancers
David W. Schoppy, Eric J. Brown
David W. Schoppy, Eric J. Brown
Published March 26, 2012
Citation Information: J Clin Invest. 2012;122(4):1202-1205. https://doi.org/10.1172/JCI63205.
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Commentary

Chk’ing p53-deficient breast cancers

Abstract

Loss or functional impairment of p53 occurs in many human cancers, and its absence is often associated with a poor response to conventional chemotherapy. Hence, much effort is currently devoted to developing novel treatments for p53-deficient malignancies. One approach is to target pathways that are selectively required for the survival of p53-deficient cancer cells, thus exploiting a synthetic lethal interaction. Previous studies have demonstrated that inhibition of the ataxia telangiectasia and Rad3-related (ATR) and checkpoint kinase 1 (Chk1) pathway in p53-deficient cells can induce such a synthetic lethal outcome. In this issue of the JCI, Ma et al. take these findings a step closer to the clinic by demonstrating that highly specific inhibitors of Chk1 synergize with chemotherapy to stem progression of p53-deficient triple-negative breast cancers in a xenotransplant model of this disease. Together with other recent studies, this report highlights the promise of ATR and Chk1 inhibitors in targeted cancer treatment.

Authors

David W. Schoppy, Eric J. Brown

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Figure 1

Proposed means by which p53 deficiency and oncogenic stress sensitize cancer cells to ATR/Chk1 inhibition.

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Proposed means by which p53 deficiency and oncogenic stress sensitize ca...
(A) Checkpoint short circuit. Loss of control of both the G2-M and G1-S checkpoints through ATR/Chk1 pathway inhibition and p53 loss, respectively, leads to increased damage through reiterative cycles into S phase and through mitosis, ultimately resulting in cell death. (B) Oncogenic stress. Oncogenic stress produces an increased reliance on the ATR/Chk1 pathway to prevent replication fork collapse into DNA double-strand breaks. Synergistic increases in DNA damage following ATR/Chk1 inhibition in oncogene-transformed cells are generated within individual cell cycles (13–17).