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.
David W. Schoppy, Eric J. Brown