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
• Journal: The Journal of clinical investigation (J Clin Invest) Vol. 122 Issue 4 Pg. 1202-5 (Apr 2012) ISSN: 1558-8238 [Electronic] United States
• PMID: 22446183 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Comment)

Chemical References

• 3-(carbamoylamino)-5-(3-fluorophenyl)-N-(3-piperidyl)thiophene-2-carboxamide
• Antineoplastic Agents
• Neoplasm Proteins
• Protein Kinase Inhibitors
• TP53 protein, human
• Thiophenes
• Tumor Suppressor Protein p53
• 7-hydroxystaurosporine
• Urea
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1
• Staurosporine

Topics

• Animals
• Antineoplastic Agents (therapeutic use)
• Breast Neoplasms (drug therapy)
• Checkpoint Kinase 1
• Female
• Humans
• Molecular Targeted Therapy
• Neoplasm Proteins (antagonists & inhibitors)
• Protein Kinase Inhibitors (therapeutic use)
• Protein Kinases (drug effects)
• Staurosporine (analogs & derivatives, therapeutic use)
• Thiophenes (therapeutic use)
• Tumor Suppressor Protein p53 (deficiency)
• Urea (analogs & derivatives, therapeutic use)