Olaparib, known by the brand name Lynparza, is a targeted cancer therapy called a PARP inhibitor that works against cancers with a specific weakness in their DNA repair. Unlike traditional chemotherapy, Olaparib selectively targets cancer cells by exploiting this vulnerability. This class of medication prevents cancer cells from fixing damage to their genetic material, a process often compromised in certain tumors.
The Role of PARP in DNA Repair
Our cells constantly face DNA damage from normal metabolic activities or environmental factors. Thousands of these events occur daily in each cell, with a common type being a single-strand break, where only one side of the DNA double helix is broken. To manage this, cells use a repair system where poly (ADP-ribose) polymerases, or PARP, are primary proteins.
The most abundant of these, PARP1, acts as a first responder to DNA damage. When a single-strand break occurs, PARP1 detects the damage and binds directly to the broken DNA site. This binding activates the PARP1 enzyme, which then uses a molecule called NAD+ to build a chain of poly (ADP-ribose) or PAR. This PAR chain acts as a signal, recruiting other DNA repair proteins to the location of the break.
These recruited proteins form a repair complex and fix the single-strand break. Once the repair is complete, the PARP1 enzyme detaches from the DNA, and the PAR chain is dismantled. This response system is important for maintaining the genetic integrity of all cells, ensuring minor DNA lesions are mended before they cause significant problems during cell division.
The Concept of Synthetic Lethality
The effectiveness of Olaparib is rooted in a biological principle known as synthetic lethality. This concept describes a situation where a cell can survive with a defect in either one of two separate genes, but the simultaneous loss or inactivation of both genes leads to cell death.
In the context of certain cancers, the first defect involves mutations in genes such as BRCA1 and BRCA2. These genes are part of a DNA repair process called homologous recombination, which is the main mechanism cells use to fix a more severe type of damage: double-strand breaks. When both strands of the DNA helix are severed, it is a dangerous lesion that can lead to genetic instability if not repaired correctly.
Cells with a harmful mutation in BRCA1 or BRCA2 have a compromised ability to perform this repair. This defect makes the cancer cell vulnerable, as it can no longer accurately fix double-strand breaks. However, the cell can still survive because its other repair pathways, including the PARP-mediated system for fixing single-strand breaks, remain functional. This dependency on the PARP pathway is the weakness that makes these cancer cells a target.
How Olaparib Induces Cancer Cell Death
Olaparib works by introducing the second, fatal defect into this already vulnerable system. The drug is an inhibitor that blocks the activity of the PARP enzymes, particularly PARP1 and PARP2. When Olaparib is present, it binds to the PARP enzyme, preventing it from properly building the PAR signal chain after it has detected a single-strand break. This inhibition has a dual consequence for the cancer cell.
The primary mechanism is known as “PARP trapping,” where the inhibited PARP enzyme becomes physically stuck on the DNA at the site of the single-strand break. These trapped PARP-DNA complexes are toxic and act as physical roadblocks. When the cell attempts to replicate its DNA during the division process, the replication machinery collides with these roadblocks, causing the replication fork to stall and collapse. This collapse results in the formation of numerous double-strand breaks.
Here, the first defect becomes important. In a healthy cell without a BRCA mutation, the homologous recombination pathway would repair these newly formed double-strand breaks, and the cell would survive. However, in the cancer cell with the defective BRCA gene, this repair pathway is non-functional. The cell is unable to fix the large number of double-strand breaks caused by the trapped PARP enzymes. This irreparable DNA damage triggers a process called apoptosis, or programmed cell death, which kills the cancer cell.
Cancers Targeted by Olaparib
Olaparib is most effective against tumors that have pre-existing defects in their DNA damage response pathways, particularly those involving homologous recombination. For this reason, Olaparib is frequently used to treat specific types of ovarian, breast, prostate, and pancreatic cancers, as these malignancies have a higher incidence of mutations in the BRCA1 and BRCA2 genes.
A patient’s tumor may have a germline mutation, meaning it was inherited, or a somatic mutation, which occurred spontaneously within the tumor cells. In either case, the presence of these BRCA mutations serves as a biomarker, predicting that the cancer cells will be susceptible to PARP inhibition.
The application of Olaparib is not strictly limited to cancers with BRCA1/2 mutations. Some cancers have other genetic or epigenetic alterations that impair homologous recombination, a state referred to as “BRCAness”. These tumors, despite lacking a direct BRCA mutation, exhibit similar deficiencies in DNA repair. As a result, they are also vulnerable to the synthetic lethal interaction created by PARP inhibitors, broadening the potential clinical use of Olaparib and similar drugs.