Endocrine-Related Cancer

Mechanisms of PARP inhibitor resistance in BRCA1/2-associated cancers. Loss of PARP inhibitor resistance in BRCA1/2 mutated cancers can occur via (1) restoration of BRCA1/2 function and HR by secondary intragenic BRCA1/2 mutations, expression of hypomorphic BRCA1 alleles, stabilisation of mutant BRCA proteins and demethylation of the BRCA1 promoter; (2) restoration of HR as a result of relief from 53BP1-mediated block on end-resection (only in BRCA1 mutant tumour cells); (3) protection of replication forks, from MRE11-mediated degradation, due to loss of PTIP, CHD4 or PARP1 expression; and (4) increased efflux of PARP inhibitor from cancer cells as a result of increased P-glycoprotein expression.