Inibidores da PARP: do mecanismo de ação à prática clínica

Abstract

Repairing damage and errors that occur in the DNA molecule is essential to maintain the integrity of the genome and cell viability. Deficits in DNA repair mechanisms lead to an increased risk of genetic instability and contribute to neoplastic transformation. Poly (ADP-ribose) polymerases (PARP) are a group of enzymes that play a key role in signalling and repairing DNA errors. The inhibition of its activity is a therapeutic strategy that takes advantage of the mechanism of synthetic lethality and that can be used in the treatment of tumours with specific defects in DNA repair pathways, namely in tumours with mutations in the tumour suppressor genes BRCA1 and BRCA2. There are several PARP inhibitors (iPARP), already approved by the USA Food and Drug Administration and the European Medicines Agency used in the treatment of breast, ovarian, pancreatic and prostate cancer. However, as with other target therapies, despite being well tolerated and widely used in the clinical practice, iPARP resistance is common and can be developed through various molecular mechanisms. In this article, we intend to make an updated review on iPARP and its main role in tumour cells, highlighting the several resistance mechanisms that have been recently revealed, as well as the current clinical applications and toxicity associated with this target therapy.

Efficacy of Spinal Cord Stimulation Using Differential Target Multiplexed Stimulation for Intractable Pain of Hereditary Neuropathy with Liability to Pressure Palsies: A Case Report

“…Fibromyalgia syndrome is a widespread pain disorder thought to have altered central pain processing. 18 , 19 ) HNPP with whole-body pain may overlap the fibromyalgia criteria and potentially delay the diagnosis of HNPP. 8 )…”

Entecavir: A Review and Considerations for Its Application in Oncology

“…According to Sherin et al, in silico studies have demonstrated that ETV could potentially be a candidate for breast, ovarian, and prostate cancer treatment, because it could inhibit the enzyme PARP1 that is expressed in these tissues, which plays a crucial role in DNA signaling and DNA damage repair [12]. Therefore, by inhibiting PARP in cancer cells, there would be the accumulation of unrepaired errors that ultimately lead to cell death [12,13].…”

“…Proteins such as BRCA1, BRCA2, PALB2, ATM, CHEK1, CHEK2, and RAD51 are involved in the HR repair process, while poly(ADP-ribose) polymerases 1 and 2, referred to as PARP1 and PARP2, are associated with the BER, with some of these proteins being frequently mutated in cancer patients. PARP not only act as regulators of the identification and repair process for SSB through BER, but also play a role in repairing DSB because they promote the activation of the repair by HR while inhibiting less conservative repair pathways such as the non-homologous route end joining (NHEJ) [13,14].…”

“…In this way, PARP inhibitors are indicated for the treatment of tumors with BRCA1/2 gene mutations or tumors with BRCAness, as they exhibit deficits in HR repair. Although the functional loss of one of the genes BRCA or PARP is compatible with cell viability, inhibiting PARP in cells with BRCA mutations renders them incapable of repairing DNA damage, leading to the accumulation of errors that ultimately lead to cell death [13,14]. Therefore, if it is indeed confirmed that ETV acts as a PARP inhibitor, it will always be relevant to conduct a genetic study of the patients to analyze the BRCA1 and BRCA2 genes.…”

Synthetic Lethality by Co-Inhibition of Androgen Receptor and Polyadenosine Diphosphate-Ribose in Metastatic Prostate Cancer

“…Deleterious alterations in genes involved in homologous recombination repair (HRR) are usually associated with an aggressive phenotype of PC but might also convey sensitivity to treatment with polyadenosine diphosphate-ribose (PARP) inhibitors (PARPi) through a mechanism of “synthetic lethality”, a phenomenon which occurs when the combination of two genetic events results in cell death, whereas a deficiency of only one of these genes does not [ 25 ]. PARPi are molecules targeting a specific DNA damage repair system, leading tumoral cells to irreparable injury and subsequent death [ 26 , 27 , 28 ]. In PC, olaparib is approved by the European Medicines Agency (EMA) in patients with mCRPC and BRCA 1/2 mutations (germline and/or somatic) who have progressed following prior therapy, including ARPI [ 29 ].…”