Understanding causes, consequences proves vital to develop therapies that exploit vulnerabilities of the cancer cells.
There have been several advances in the field of somatic and tumor genetics in recent years.
One has been the discovery of tumors harboring deficiencies in the homologous recombination repair (HRR) pathway. This pathway takes place during the S and G2 phase of the cell cycle and is primarily responsible for repair of the originating DNA sequence at the site of double strand (ds) DNA breaks.1 The HRR pathway is considered a high-fidelity pathway, with a high degree of accuracy in repairing dsDNA breaks during normal meiosis. When the HRR pathway is compromised, other low-fidelity pathways, such as the nonhomologous DNA end joining and microhomology-mediated end joining pathways, are utilized. These low-fidelity pathways often result in loss of genetic information and allelic imbalance and leave a genetic scar.2
Among the most common causes of disruption to the HRR pathway are mutations in homologous recombination genes, such as the BRCA1 and BRCA2 genes, commonly found in individuals with hereditary breast and ovarian cancer syndromes and are associated with an increased risk of developing multiple types of other cancers.3 Other common genes involved in the HRR pathway that can be mutated or silenced, leading to HRR deficiency, include PALB2, RAD51C, and RAD51D.2
The role of HRR deficiency in cancer development has been vital to the advancement of several cancer therapies. One therapeutic approach of these targeted therapies has been to specifically inhibit the function of proteins involved in the HRR pathway. A characteristic example of this takes place with a class of medications called PARP inhibitors, which are commonly used in patients with breast and ovarian cancer harboring BRCA1 or BRCA2 mutations. BRCA1 and BRCA2 are tumor suppressor genes that play a critical role in the dsDNA break repair by signaling for the recruitment of repair enzymes or binding to the site of DNA damage to initiate repair. BRCA1 and BRCA2 mutations (either germline or somatic) lead to dysfunction in the homologous recombination DNA repair pathway and ultimate reliance on error-prone and low-fidelity pathways of DNA repair. On the other hand, another critical element of the DNA-repair process involves PARP-1 and PARP-2. These enzymes are activated in response to DNA breaks as well. In this case, the polymerase uses nicotinamide adenine dinucleotide to catalyze the addition of ADP-ribose polymers onto DNA, histones, and other DNA repair proteins, resulting in DNA break repair. When this process is hindered by the use of a PARP inhibitor, the concept of synthetic lethality causes ultimate cell death. Synthetic lethality is a concept that entails 2 nonlethal genetic defects that are ultimately lethal when combined. In this example, BRCA1- and BRCA2-deficient tumor cells, which lack the ability to repair the accumulating double-strand DNA damage, in addition to PARP inhibition, via a PARP inhibitor, lead to chromatic instability and promotion of cell death.4
There are several PARP inhibitors that are FDA approved for the treatment of various cancers. These include niraparib, olaparib, rucaparib, and talazoparib. Although these agents have a similar mechanism, they differ in their FDA-approved indication, place in therapy, drug interactions, dosing, and toxicity profile. Some of the most common toxicities associated with PARP inhibitors include anemia, constipation, fatigue, increased serum creatinine, nausea, neutropenia, and thrombocytopenia.5
Understanding the causes and consequences of HRR deficiency is key for the development of therapies to exploit the vulnerabilities of HRR deficiency in cancer cells. In addition to FDA-approved medications, several therapies that target the HRR pathway are being developed and tested in clinical trials, representing a step forward in treatment.
About the Author
Elizabeth A. Hansen, PharmD, BCOP is the clinical pharmacy program manager of oncology for VISN 12 Pharmacy Benefits Management, US Department of Veterans Affairs in Columbus, Ohio.