Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) are now a first-line maintenance treatment in ovarian cancer and have been approved in other cancer types, including breast, pancreatic and prostate. Despite their efficacy, and as is the case for other targeted therapies, resistance to PARPi has been reported clinically and is generating a growing patient population of unmet clinical need. Here, we discuss the mechanisms of resistance that have been described in pre-clinical models and focus on those that have been already identified in the clinic, highlighting the key challenges to fully characterise the clinical landscape of PARPi resistance and proposing ways of preventing and overcoming it.
Highlights
The discovery more than 15 years ago of a synthetic lethal (SL) relationship between mutations in the breast cancer susceptibility, tumour-suppressor genes BRCA1 and BRCA2 and the inhibition of poly(ADP-ribose) polymerase (PARP) enzymes [1,2] spearheaded the clinical development of PARP inhibitors (PARPi)
Have proven very useful methods to identify patients that could benefit from PARPi, it is important to highlight that both methodologies rely on the detection of genetic mutations or the assessment of genomic instability that are a historical account of the BRCA/HRD status of the tumour
Analyses of paired biopsies pre- and post-platinum progression of ovarian tumours have shown that the de-silencing of BRCA1 is linked to platinum resistance [31]. No such correlation has yet been established in post-PARPi clinical progressions, but it has been identified in several cases of acquired PARPi resistance in patient-derived xenograft (PDX) models of breast [39,55]
Summary
The discovery more than 15 years ago of a synthetic lethal (SL) relationship between mutations in the breast cancer susceptibility, tumour-suppressor genes BRCA1 and BRCA2 and the inhibition of poly(ADP-ribose) polymerase (PARP) enzymes [1,2] spearheaded the clinical development of PARP inhibitors (PARPi). In the case of gBRCA2m, this extends to prostate and pancreatic cancer [4,5] Tumours of these patients almost universally lose both functional copies of the BRCA1 or BRCA2 gene, either by loss of heterozygosity (LOH) of the wild-type allele or, more rarely, by the acquisition of a somatic mutation in the wild-type locus [6]. (EMT)isischaracterised characterisedby bythe theloss lossof ofcell–cell cell–cellininterEpithelial–mesenchymal transition
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