Resistance to PARP inhibitors may be innate or acquired. Innate resistance occurs when PARP inhibitors are ineffective from the start of treatment, due to pre-existing resistance mechanisms. Acquired resistance occurs when PARP inhibitors become ineffective during the course of treatment and after a clinical benefit has been observed.
In some clinical trials, subsets of patients have been identified who experienced a long-term response (>2 years) to treatment with the PARP inhibitor olaparib; analysis of these patients might provide insights into preventing resistance . Long-term responses occurred in patients with or without an identified BRCA mutation, but did correlate with a complete response to preceding chemotherapy .
The main clinically relevant mechanisms thought to confer resistance to PARP inhibitor treatment are:
1. Existence or restoration of HRR functionality
- Re-expression of BRCA1 variants can occur via secondary reversion mutations that restore the original open reading frame and consequently the function of BRCA1, BRCA2, PALB2or RAD51C (which is also responsible for resistance to platinum) [2-8].
- Patients without BRCA reversion mutations have been found to have significantly longer progression-free survival in response to rucaparib .
2. Hypomorphic forms of BRCA1 (eg BRCA1-C61G; BRCA1-11q alternative splice isoform; the RING-less BRCA1 generated by downstream translation initiation) may result in partial restoration of HRR [10, 11].
3. Epigenetic changes in HRR genes have also been shown to contribute to PARP inhibitor sensitivity and resistance [5, 12, 13].
- Promoter hypermethylation of genes such as BRCA1 and RAD51C results in lack of mRNA expression, HRD and PARP inhibitor sensitivity
- Their subsequent demethylation can be associated with protein re-expression and development of resistance
4. Loss of PARP1 function has been associated with development of PARP resistance both clinically and preclinically . A PARP1 mutation identified in the tumour of a PARP-resistant patient prevented PARP trapping, linking resistance to PARP with loss of PARP-trapping ability .
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