Breast cancer is the leading form of cancer in women, with 2.26 million new cases diagnosed in women in 2020 (IARC, 2023). Certain factors increase one’s risk for breast cancer, such as obesity and smoking. Another prominent risk factor is hereditary mutations (Cohen, et al., 2023), including within the BReast CAncer (BRCA) genes.
BRCA genes are tumour-suppressor genes. They are heavily involved in repairing a type of DNA break called double-strand breaks (DSBs) in the repair pathway of homologous recombination, otherwise known as HR (Mehrgou and Akouchekian, 2016). Without them, the body switches to other pathways such as non-homologous end joining, which is more error-prone and can thus lead to more harmful mutations that cause cancer.
Poly-ADP ribose polymerase (PARP) inhibitors are a class of drugs used to treat cancers, including breast cancer. PARP is a protein involved in the base-excision repair (BER) pathway. It finds DNA damage in the form of single-strand breaks (SSBs), binds to it, and creates a chain of poly-ADP ribose (PAR). PAR then signals DNA repair proteins to fix the break. However, if a PARP inhibitor is introduced into the body, PARP can no longer complete this repair pathway (Zheng, et al., 2020). Figure 1 illustrates this process.
Figure 1: PARP inhibitors disrupt the normal BER pathway carried out by the PARP protein, leading to cell death (apoptosis) in some cells. However, if a cell had a functioning HR pathway, it would continue to survive. So, the drug will only kill the cells with a damaged HR pathway (Zheng, et al., 2020).
After replication, the SSBs become DSBs. This is favourable to BRCA mutation-carriers due to synthetic lethality, where 2 systems (i.e., HR and BER pathways) failing separately will not cause cell death, but together will result in apoptosis (Neiger, Siegler and Shi, 2021). So, the tumour cells with the BRCA mutations will be eliminated.
One type of PARP inhibitor is Olaparib. It is an antineoplastic agent: a drug used to treat cancer (PubChem, 2023). The chemical structure of it is seen in Figure 2.
Figure 2: Chemical structure of Olaparib. It is created by condensing the carboxy group of 2-fluoro-5-[(4-oxo-3,4-dihydrophthalazin-1-yl) methyl] benzoic acid with the free amino group of N-(cyclpropylcarbonyl)piperazine (PubChem, 2023).
The efficacy of Olaparib is seen in many studies. For instance, Robson et al.’s study shows how the risk of disease progression or death was 42% lower in their cohort of BRCA-mutated breast cancer patients treated with Olaparib than those without, indicating the viability of Olaparib as a treatment for BRCA-mutated breast cancer (Robson, et al., 2017).
However, there have been concerns about the disadvantages of Olaparib. Some side effects include nausea, vomiting, and diarrhea (Penson, et al., 2020). Beyond these short-term effects, the continual use of PARP inhibitors like Olaparib can result in resistance. Sakai W et al.’s study shows how patients can have their mutational reading frame (the genetic code used to create proteins) changed because the PARP protein is no longer active to prevent certain harmful mutations, leading to more BRCA2 wild-type mutations (Sakai, et al., 2008). There needs to be more research to gain a consensus on whether PARP inhibitors such as Olaparib are an effective treatment for breast cancer.
PARP inhibitors such as Olaparib are a viable class of drugs with the potential to treat BRCA-mutated breast cancer in patients. Although there have been studies detailing the efficacies and consequences of these drugs, more research is needed to understand the effects of them in various individuals.
References
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Inernational Agency for Research on Cancer (IARC), 2023. Breast cancer – IARC. [online] Available at: <https://www.iarc.who.int/cancer-type/breast-cancer/> [Accessed 13 September 2023].
Mehrgou, A. and Akouchekian, M., 2016. The importance of BRCA1 and BRCA2 genes mutations in breast cancer development. Medical Journal of the Islamic Republic of Iran, 30, p.369. https://doi.org/10.1016/j.biopha.2019.109661.
Neiger, H.E., Siegler, E.L. and Shi, Y., 2021. Breast cancer predisposition genes and synthetic lethality. International Journal of Molecular Sciences, 22(11), p.5614. https://doi.org/10.3390/ijms22115614.
Penson, R.T., Valencia, R.V., Cibula, D., Colombo, N., Leath, C.A., Bidziński, M., Kim, J.-W., Nam, J.H., Madry, R., Hernández, C., Mora, P.A.R., Ryu, S.Y., Milenkova, T., Lowe, E.S., Barker, L. and Scambia, G., 2020. Olaparib versus nonplatinum chemotherapy in patients with platinum-sensitive relapsed ovarian cancer and a germline BRCA1/2 mutation (SOLO3): A randomized phase III trial. Journal of Clinical Oncology, 38(11), pp.1164–1174. https://doi.org/10.1200/JCO.19.02745.
PubChem, 2023. Olaparib. [online] Available at: <https://pubchem.ncbi.nlm.nih.gov/compound/23725625> [Accessed 15 September 2023].
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Sakai, W., Swisher, E.M., Karlan, B.Y., Agarwal, M.K., Higgins, J., Friedman, C., Villegas, E., Jacquemont, C., Farrugia, D.J., Couch, F.J., Urban, N. and Taniguchi, T., 2008. Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers. Nature, 451(7182), pp.1116–1120. https://doi.org/10.1038/nature06633.
Zheng, F., Zhang, Y., Chen, S., Weng, X., Rao, Y. and Fang, H., 2020. Mechanism and current progress of Poly ADP-ribose polymerase (PARP) inhibitors in the treatment of ovarian cancer. Biomedicine & Pharmacotherapy, 123, p.109661. https://doi.org/10.1016/j.biopha.2019.109661.