PARP1 inhibitors are back in the headlines this week, as Astra Zeneca’s (Cambridge, England) and Merck’s (Kenilworth, New Jersey) Lynparza posted positive Phase III results from a trial with pancreatic cancer patients—a notoriously difficult cancer to treat. Lynparza has been shown to help patients with BRCA-mutated metastatic pancreatic cancer live longer without their cancer progressing. The drug has already gained two FDA approvals for BRCA-mutated breast and ovarian cancers. This week, we’ll take a look at what PARP1 inhibitors are and their connection to BRCA-mutated cancers.
DNA DAMAGE RUNS DEEP
PARP1 inhibitors work by exploiting the cellular pathways found in DNA damage repair. So, how exactly does DNA get damaged?
DNA incurs approximately 10,000 to 1,000,000 “molecular lesions” per day from breaks or “nicks” to the double helix, or chemical modification to the A, C, G, or T bases. This may sound high—but remember, our DNA contains six billion bases (three billion base pairs), so this is equivalent to .001% to .1% of the total DNA in each cell. This damage occurs as a result of normal DNA replication errors and environmental exposures, such as ultraviolet radiation, X-rays, and chemicals.
The good news is our cells have mechanisms to fight against this damage before it causes harm. DNA repair proteins find and fix different types of DNA damage. If DNA damage exceeds a threshold amount (beyond which repair is possible) a protein called p53 triggers cell death—also known as apoptosis. DNA repair proteins prevent errant cells from turning into cancerous cells, a likely outcome if the damage accumulates in genes important for regulating cell growth and division.
Arguably the most famous DNA repair proteins, BRCA1 and BRCA2, were first discovered to be active in breast tissue, hence the moniker “breast cancer type 1/2 susceptibility,” or BRCA. If these repair proteins themselves are non-functional, the cells in which they would normally do their job are prone to sustaining DNA damage at a much higher rate than normal. This higher rate of DNA damage increases the chances of cancer developing in those cells. BRCA1/BRCA2 positive cancer is cancer that is associated with mutations in the BRCA1/BRCA2 genes. The mutations are most strongly associated with breast and ovarian cancer, but are also associated with increased risk of developing stomach, pancreatic, prostate, melanoma, leukemia, lymphoma, and colon cancer. (Article continues below)
THE POINT OF PARP
PARP1 is a DNA repair protein. By stopping the PARP1 repair pathway in cells already deficient in BRCA1/BRCA2-mediated repair, cancer cells become extremely vulnerable to DNA damage. Because of this, DNA damage accumulates and triggers apoptosis. A PARP1 inhibitor is usually administered in combination with chemotherapy or radiation therapy, which increases the incidence of apoptosis-triggering DNA damage. Healthy cells, which still have BRCA repair pathways intact, are less sensitive to additional DNA damage.
Preclinical research suggests that PARP1 inhibitors may also be relevant to other disease areas, such as autoimmune and inflammatory disorders. PARP1 has been shown to play a role in activating proteins that drive inflammation. Preclinical models demonstrate that in cases without the PARP1 gene, subjects were less vulnerable to rheumatoid arthritis than with the gene. Inhibiting PARP1 resulted in reduced signs of inflammation in models of multiple sclerosis, irritable bowel disease, and allergic airway inflammation.
EASILY CONFUSED: DNA DAMAGE VS. DNA MUTATION
BRCA1, BRCA2, PARP1, and other DNA-repair proteins correct DNA damage, but they don’t fix mutations. What’s the difference?
DNA damage refers to alterations in the chemical structure of DNA. This may mean a break in the DNA strand, a substitution to one of the bases that make up DNA (A, C, G, or T), or even a missing base. These changes are detected and corrected by DNA repair enzymes.
A DNA mutation is a change to the actual base sequence (A, C, G, or T). Mutations can arise if DNA damage is not corrected. Recall that in undamaged DNA, an “A” base always pairs with a “T” base, and a “C” base always pairs with a “G” base. These base-pairing rules are what enable DNA to replicate faithfully from one generation of cells to the next. However, uncorrected DNA damage may cause that “A” base to mistakenly pair with a “G” during replication; or a “C” to pair with a “T.” This results in a sequence change —a mutation—in the replicated DNA. The gene now provides incorrect genetic information to the cell.