Concept of synthetic lethality: PARP inhibitors – New era in personalized medicine
The term “synthetic lethality” was originally coined by geneticists in the 1940s. It arises when a combination of deficiencies in the expression of two or more genes leads to cell death, whereas a deficiency in only one of these genes does not. Although the concept originated some 8 decades ago, it was applied to cancer somewhat later to explain the selective killing of cancer cells with particular molecular defects. Only simultaneous mutations in gene pair confer lethality while any other combination of mutations is viable (as conceptualized in fig 1).
Normally in response to DNA damage, the PARP pathway and BRCA tumor suppressor proteins are activated which repair the damaged DNA. Cells with BRCA mutations become dependent on the PARP pathway to fix damages to DNA, since the protein product of BRCA genes is altered and defective. Cells exposed to PARP inhibitors repair DNA via the protein products encoded by BRCA genes if they become damaged. In cells with BRCA mutations that are treated with PARP inhibitors, both DNA repair mechanisms are blocked and the cell dies (as conceptualized in figure 2)
Based upon this concept since the inception of various human clinical trials the earliest success was achieved by the PARP inhibitor olaparib. It got accelerated approval in 2014 for treatment of relapsed BRCA-mutated advanced ovarian cancer. As of today olaparib is used in germline/somatic BRCA mutated breast, ovarian, pancreatic and prostate cancer either as a maintenance or palliative treatment. There are number of other PARP inhibitors which are under clinical development, few of these are already approved for various other indications. Other PARP inhibitors approved in various indications are rucaparib, niraparib, velaparib and talazoparib. These newer agents have drastically changed the outlook of these BRCA mutated cancers significantly increasing either overall survival or progression free survival. Apart from BRCA mutated cancers some of these agents are also active in homologous recombinant deficient cancers (HRD) which is an enzyme system analogous to BRCA. PARP inhibitors show promise as a powerful therapeutic tool, where these genes may be dysfunctional clearly signifying a new era in personalized medicine.