Role of PARP Inhibitors in BRCA-Related Malignancies

Sana Iqbal, PharmD; Mohammad A. Rattu, PharmD, BCOP, BCPS, BCGP; Neal Shah, PharmD

Disclosures

US Pharmacist. 2018;43(9):HS10-HS17. 

In This Article

Drug Resistance

Acquired resistance to PARP inhibitors is increasing, and proposed mechanisms include 1) BRCA gene mutations could reverse and restore homologous recombination functions; 2) Nonhomologous end-joining functions may decrease, causing DSBs to be more accurately repaired through homologous recombination; 3) PARP levels or activity may decrease, leading to decreased target sites for PARP inhibitors; 4) P-glycoprotein efflux pumps may upregulate and remove PARP inhibitors from cells; 5) RAD51 activity may increase, which is a biomarker for homologous recombination function.[3]

On the other hand, when ATR kinase is inhibited, BRCA1-independent homologous recombination and fork protection decrease, leading to a cell's resensitizing to PARP inhibitors. Therefore, ATR inhibitors represent a potentially new drug class to overcome PARP-inhibitor resistance in BRCA-deficient malignancies.[28]

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