Mechanism Of Action Of Parp Inhibitors
PARP Inhibitors for Prostate Cancer
The original rationale for using PARPi as a cancer treatment is that PARPi can sensitize tumor cells to therapies that cause DNA damage, such as chemo or radiotherapy. The inhibition of PARP-mediated repair of DNA damage produced by chemotherapy or radiotherapy, may result in an increased of therapeutic potency . Almost two decades ago, two groups described the important concept of Synthetic Lethal interaction between PARP inhibition and BRCA1 or BRCA2 mutation, which represented a new therapeutic option for BRCA-mutant tumors . SL means that a defect in either one of two genes has little effect on the organism, but a combination of defects in both genes results in cell death. Carriers of deleterious heterozygous germline mutations in the BRCA1 and BRCA2 genes have high risk of different types of cancer, such as PCa . BRCA1 and BRCA2 are tumor-suppressor genes involved in transcriptional regulation and, as stated before, are critical to the repair of DSBs in the DNA molecule, playing a key role in the HR pathway . Cells with functional loss in these genes are unable to repair errors in DNA, depending on PARPs ability to detect these damages and activate alternative repair pathways. PARPi antitumor activity is based on the concept of synthetic lethality, in which two separate molecular pathways, which are not lethal when disrupted individually, cause cell death when inhibited simultaneously . PARPi Trapping Potency. Ddr Mutations And Prostate CancerA number of studies have reported the frequencies of somatic and germline mutations in DDR genes at several disease stages of PCa, but whether or not patient mutation status indicates clinical benefit has yet to be seen . In 2015, Robinson et al. evaluated 150 cases of mCRPC and found that 22.7% of tumors harbored deleterious DDR germline or somatic mutations in BRCA1, BRCA2, ATM, CDK12, FANCA, RAD51B, and RAD51C . Pritchard et al. found that 11.8% of screened patients with mCRPC had at least one germline mutation in a DDR gene , and Abida et al., in 2017, found that 27% of screened patients across all stages of PCa possessed germline or somatic alterations in either BRCA1/2, ATM, and CHEK2 . The recent PROfound trial screened 4,425 patients with mCRPC for 15 genes with direct or indirect roles in HR. A total of 2,792 patients were successfully sequenced, and qualifying alterations were found in 778 of 2,792 patients . These reported frequencies in sequenced patients have been corroborated by several other studies in mCRPC , as seen in . Frequencies of germline vs. somatic mutations in DNA damage repair genes and evidencebased clinical applications in prostate cancer
Parp Inhibitors: From Bench To BedsidePoly polymerases , a family of enzymes sharing a catalytical domain whose main function is to add poly-ADP-ribose chains to other proteins as signaling transmitter and/or to regulate transcription. PARP1, predominantly, and PARP2, are critical to DNA single-strand break repair. They detect ssDNA breaks, bind to them and synthesize PAR using NAD+, initiating the call for DNA repair mediators and effectors, which then will require PARP1/2 to be removed from the site of damage for the ssDNA repair process to properly ensue. PARP inhibitors are drugs that compete with NAD+ to bind to the enzyme, and therefore prevent proper activation of the ssDNA break repair cascade. Unrepaired ssDNA breaks will progress to double-strand DNA breaks. However, cells have specific pathways to repair toxic dsDNA breaks, including the error-prone non-homologous end joining and microhomology-mediated end joining pathways and the preferred, error-free, homologous recombination repair pathway. Recommended Reading: Psa Test Vs Prostate Exam Mechanisms Of Intrinsic And Acquired Resistance To Parp InhibitorsSimilar to other targeted therapies, resistance to PARPi has been observed in most patients with advanced tumors . There are several mechanisms for resistance proposed so far that demonstrate how tumor cells stop responding to the cytotoxic effects of PARPi, and can be grouped as follows:
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