INDUCTION OF ALTERNATIVE APOPTOTIC PATHWAY BY INHIBITION OF CHK1 IN CANCER CELLS HARBORING P53 AND BCL2 MUTATIONS
Resistance, chemo- and radiotherapy
combinations of CHK1 inhibitors with genotoxic stress may be more effective in patients with defective p53 genotype. In addition, monitoring of Caspase 2 activation in tumor samples may be prognostic factor for patient response for such combination therapy.
The Dana-Farber investigators discovered a novel approach to kill cancer cells that are otherwise resistant to conventional therapies due to mutations in pro-apoptotic (p53) or pro-survival (BCL2) pathway components. This death mechanism is induced when radio- or chemotherapy are combined with inhibitors targeting cell cycle check point molecule CHK1. Such treatment triggers a caspase-2-dependent apoptotic program that bypasses p53 deficiency and excess Bcl-2. The discovery was made by screening in p53 mutant zebrafish embryos and re-evaluated in human cancer cells.
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