PARP Inhibitors: Clinical Relevance, Mechanisms of Action and Tumor Resistance

Pancreatic cancer is the seventh leading cause of cancer-related deaths worldwide. However, its toll is higher in more developed countries. Reasons for vast differences in mortality rates of pancreatic cancer are not completely clear yet, but it may be due to lack of appropriate diagnosis, treatment and cataloging of cancer cases. Because patients seldom exhibit symptoms until an advanced stage of the disease, pancreatic cancer remains one of the most lethal malignant neoplasms that caused 432,242 new deaths in 2018 (GLOBOCAN 2018 estimates). Globally, 458,918 new cases of pancreatic cancer have been reported in 2018, and 355,317 new cases are estimated to occur until 2040. Despite advancements in the detection and management of pancreatic cancer, the 5-year survival rate still stands at 9% only. To date, the causes of pancreatic carcinoma are still insufficiently known, although certain risk factors have been identified, such as tobacco smoking, diabetes mellitus, obesity, dietary factors, alcohol abuse, age, ethnicity, family history and genetic factors, Helicobacter pylori infection, non-O blood group and chronic pancreatitis. In general population, screening of large groups is not considered useful to detect the disease at its early stage, although newer techniques and the screening of tightly targeted groups (especially of those with family history), are being evaluated. Primary prevention is considered of utmost importance. Up-to-date statistics on pancreatic cancer occurrence and outcome along with a better understanding of the etiology and identifying the causative risk factors are essential for the primary prevention of this disease.

To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation-the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.

Olaparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, has previously shown efficacy in a phase 2 study when given in capsule formulation to all-comer patients with platinum-sensitive, relapsed high-grade serous ovarian cancer. We aimed to confirm these findings in patients with a BRCA1 or BRCA2 (BRCA1/2) mutation using a tablet formulation of olaparib.