PARP Inhibitors Resistance: Mechanisms and Perspectives

Abstract

PolyADP-ribose polymerase (PARP) inhibitors (PARPis) represent the first clinically approved drugs able to provoke “synthetic lethality” in patients with homologous recombination-deficient (HRD) tumors. Four PARPis have just received approval for the treatment of several types of cancer. Besides, another three additional PARPis underlying the same mechanism of action are currently under investigation. Despite the success of these targeted agents, the increasing use of PARPis in clinical practice for the treatment of different tumors raised the issue of PARPis resistance, and the consequent disease relapse and dismal prognosis for patients. Several mechanisms of resistance have been investigated, and ongoing studies are currently focusing on strategies to address this challenge and overcome PARPis resistance. This review aims to analyze the mechanisms underlying PARPis resistance known today and discuss potential therapeutic strategies to overcome these processes of resistance in the future.

Biomarkers of Homologous Recombination Deficiency in the era of PARP inhibitors

“…Hence, analysing feasibility of functional assays on multiple and serial samples obtained from liquid biopsy could majorly impact in clinical decision-making in the recurrent setting. Several mechanisms of resistance to PARPi have been suggested, with only reversions in BRCA1/2 clinically proved; however, other mechanism different from HR restoration have been described in preclinical models (85). Moreover, several ongoing clinical trials are investigating the combination of PARPi (especially Olaparib) with inhibitors of the replication stress, particularly ATR inhibitors (86), in order to elicit additive or synergistic effects and possibly overcome PARPi resistance.…”

Clinical implications and practical considerations for poly-ADP-ribose polymerase inhibitors as a new horizon for the management of urothelial carcinoma of the bladder

“…In patients with HRD, DSBs can be repaired only through NHEJ, an error-prone pathway that leads to genomic instability, mitotic damage, and cell death, consequently provoking “synthetic lethality”. PARP inhibitors (PARPi) block the repair of DNA SSBs, and for tumors with HRD, they cause cell death due to inefficient cell repair mechanisms [ 2 3 4 ].…”

“…Since 2014, four PARPi (olaparib, niraparib, rucaparib, and talazoparib) have been approved by the Food and Drug Administration and the European Medicines Agency for clinical use in several cancers with HRD, including breast, ovarian, prostate, and pancreatic cancers [ 2 3 4 ]. Based on pivotal phase II and III trials, olaparib and rucaparib have recently received breakthrough approval for metastatic castration-resistant prostate cancer carrying germline or somatic aberrations in genes related to HRR that progressed following prior therapy that included a next-generation hormonal therapy.…”

“…To evaluate the benefits of PARPi in a/m UCB, it is urgent to identify novel and reliable biomarkers that can detect HRD in tumor specimens or the germlines. Deleterious mutations in BRCA1 or BRCA2 gene are a canonical example of HRD [ 1 2 3 4 17 ]. However, HRD can also occur through methylation changes in other HRR genes that decrease gene expression or epigenetic silencing without canonical HRR gene mutations.…”

“…At present, three types of HRD testing methods including HRR gene-level tests, identification of genomic scars or mutational signatures and functional assays that can indicate HRD have been suggested [ 1 2 3 4 6 7 18 ]. The myChoice ® CDx HRD assay (Myriad Genetics, Salt Lake City, UT, USA) and FoundationOne CDx (Foundation Medicine, Cambridge, MA, USA) assays are the only NGS-based, prospectively validated, and commercially available tests for HRD status assessment.…”