Leveraging PARP-1/2 to Target Distant Metastasis

Abstract

Poly (ADP-Ribose) Polymerase (PARP) inhibitors have changed the outcomes and therapeutic strategy for several cancer types. As a targeted therapeutic mainly for patients with BRCA1/2 mutations, PARP inhibitors have commonly been exploited for their capacity to prevent DNA repair. In this review, we discuss the multifaceted roles of PARP-1 and PARP-2 beyond DNA repair, including the impact of PARP-1 on chemokine signalling, immune modulation, and transcriptional regulation of gene expression, particularly in the contexts of angiogenesis and epithelial-to-mesenchymal transition (EMT). We evaluate the pre-clinical role of PARP inhibitors, either as single-agent or combination therapies, to block the metastatic process. Efficacy of PARP inhibitors was demonstrated via DNA repair-dependent and independent mechanisms, including DNA damage, cell migration, invasion, initial colonization at the metastatic site, osteoclastogenesis, and micrometastasis formation. Finally, we summarize the recent clinical advancements of PARP inhibitors in the prevention and progression of distant metastases, with a particular focus on specific metastatic sites and PARP-1 selective inhibitors. Overall, PARP inhibitors have demonstrated great potential in inhibiting the metastatic process, pointing the way for greater use in early cancer settings.

Keywords: PARP inhibitors; PARP-1; PARP-2; cancer; metastasis; tumor microenvironment.

Figure 1

Role of PARP-1 in the metastatic cascade. During metastasis, PARP-1 promotes epithelial-to-mesenchymal transition (EMT) by regulating the expression of several proteins including vimentin, Snail1, and E-cadherin. PARP-1 induces the expression of matrix metalloproteases by activating the NF-κB pathway, facilitating the invasion of cancer cells through the extracellular matrix. In angiogenesis, PARP-1 regulates the transcriptional activity of HIF-1, leading to the expression of pro-angiogenic proteins. PARP-1 modulates cell migration by regulating the transcription of CCL2 through the transcriptional activity of NF-κB. PARP-1 also influences initial colonization, astrogliosis, osteoclastogenesis, angiogenesis, and EMT at distant metastatic sites, such as brain, bone, and lung.