Resistance Mechanisms

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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 [1]. Long-term responses occurred in patients with or without an identified BRCA mutation, but did correlate with a complete response to preceding chemotherapy [1].

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 [9].

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 [14]. 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 [14].

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References

1. Lheureux S, Lai Z, Dougherty BA et al. Long-Term Responders on Olaparib Maintenance in High-Grade Serous Ovarian Cancer: Clinical and Molecular Characterization. Clin Cancer Res 2017; 23: 4086-4094.
2. Barber LJ, Sandhu S, Chen L et al. Secondary mutations in BRCA2 associated with clinical resistance to a PARP inhibitor. J Pathol 2013; 229: 422-429.
3. Norquist B, Wurz KA, Pennil CC et al. Secondary somatic mutations restoring BRCA1/2 predict chemotherapy resistance in hereditary ovarian carcinomas. J Clin Oncol 2011; 29: 3008-3015.
4. Goodall J, Mateo J, Yuan W et al. Circulating Cell-Free DNA to Guide Prostate Cancer Treatment with PARP Inhibition. Cancer Discov 2017; 7: 1006-1017.
5. Kondrashova O, Nguyen M, Shield-Artin K et al. Secondary Somatic Mutations Restoring RAD51C and RAD51D Associated with Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov 2017; 7: 984-998.
6. Weigelt B, Comino-Mendez I, de Bruijn I et al. Diverse BRCA1 and BRCA2 Reversion Mutations in Circulating Cell-Free DNA of Therapy-Resistant Breast or Ovarian Cancer. Clin Cancer Res 2017; 23: 6708-6720.
7. Christie EL, Fereday S, Doig K et al. Reversion of BRCA1/2 Germline Mutations Detected in Circulating Tumor DNA From Patients With High-Grade Serous Ovarian Cancer. J Clin Oncol 2017; 35: 1274-1280.
8. Waks AG, Cohen O, Kochupurakkal B et al. Reversion and non-reversion mechanisms of resistance (MoR) to PARP inhibitor (PARPi) or platinum chemotherapy (chemotx) in patients (pts) with BRCA1/2-mutant metastatic breast cancer (MBC). J Clin Oncol 37, 2019 (suppl; abstr 1085).
9. Lin KK, Harrell MI, Oza AM et al. BRCA Reversion Mutations in Circulating Tumor DNA Predict Primary and Acquired Resistance to the PARP Inhibitor Rucaparib in High-Grade Ovarian Carcinoma. Cancer Discov 2019; 9: 210-219.
10. Bouwman P, Jonkers J. Molecular pathways: how can BRCA-mutated tumors become resistant to PARP inhibitors? Clin Cancer Res 2014; 20: 540-547.
11. Cruz C, Castroviejo-Bermejo M, Gutierrez-Enriquez S et al. RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer. Ann Oncol 2018; 29: 1203-1210.
12. Castroviejo-Bermejo M, Cruz C, Llop-Guevara A et al. A RAD51 assay feasible in routine tumor samples calls PARP inhibitor response beyond BRCA mutation. EMBO Mol Med 2018.
13. Ter Brugge P, Kristel P, van der Burg E et al. Mechanisms of Therapy Resistance in Patient-Derived Xenograft Models of BRCA1-Deficient Breast Cancer. J Natl Cancer Inst 2016; 108.
14. Pettitt SJ, Krastev DB, Brandsma I et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun 2018; 9: 1849.