Synthetic lethality of PARP inhibition in cancers lacking BRCA1 and BRCA2 mutations - UKPMC Article - UK PubMed Central
Abstract
Utilizing
the concept of synthetic lethality has provided new opportunities for
the development of targeted therapies, by allowing the targeting of loss
of function genetic aberrations. In cancer cells with BRCA1 or BRCA2
loss of function, which harbor deficiency of DNA repair by homologous
recombination, inhibition of PARP1 enzymatic activity leads to an
accumulation of single strand breaks that are converted to double strand
breaks but cannot be repaired by homologous recombination. Inhibition
of PARP has therefore been advanced as a novel targeted therapy for
cancers harboring BRCA1/2 mutations. Preclinical and
preliminary clinical evidence, however, suggests a potentially broader
scope for PARP inhibitors. Loss of function of various proteins involved
in double strand break repair other than BRCA1/2 has been
suggested to be synthetically lethal with PARP inhibition. Inactivation
of these genes has been reported in a subset of human cancers and might
therefore constitute predictive biomarkers for PARP inhibition. Here we
discuss the evidence that the clinical use of PARP inhibition may be
broader than targeting of cancers in BRCA1/2 germ-line mutation carriers.
Key words: homologous recombination, PARP inhibitor, BRCA1, BRCA2, PTEN, PALB2, EMSY, double strand break repair
