Eliana Abramowitz

Introduction. Breast Cancer Gene 1 (BRCA1) and Breast Cancer Gene 2 (BRCA2) are involved in tumor suppression.^1,3 These are high penetrance cancer suppressor genes that, when mutated, impair homologous recombination and are unable to activate DNA repair properly in the presence of cellular stress.^2,3 The cause of these mutations is diverse, including germline mutations, promoter methylations, and somatic mutations.^2,3 About 5-10% of breast cancer cases are thought to be hereditary with 50% of hereditary breast cancer cases due to BRCA1/2 mutations.^1,3BRCA breast cancer tumors present clinically as invasive ductal (75%), atypical medullary (10%) with some BRCA2 breast cancer presenting as lobular or ductal with lobular feature type (up to 10%).² BRCA1 carriers have 65% lifelong risk; BRCA2 carries have 45% lifelong risk.^2,3 Common treatments for BRCA ½ cancer include: combination surgery/radiotherapy, chemotherapy, and Poly (adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitor treatment.^1,2,4 PARP is “an abundant chromatin-associated enzyme, whose activity is strongly induced in response to genotoxic stress⁴”, and drugs that target PARP1/2 can cause synthetic lethality in homologous recombination (HR) deficient tumors.⁵ The purpose of this study is to identify the mechanisms of PARPi resistance that prevent consistency in the efficacy of treatment of BRCA 1/2. Methods. One study utilized a CRISPR-Cas9 mutagenesis screen, and then further analyzed resistant clones via a PARP trapping assay.⁵ Two studies used colony formation assay after western blot and high-content microscopy.^4,6 Lastly, a study looking to overcome PARPi resistance utilized a CMAP database to compare perturbation profiles.⁸ Results. One study found that PARP1 trapping potency correlates with the cytotoxic potency of different PARPi and that with the loss of PARP1 tumor cells are rescued from PARPi induced genotoxic stress as well as cell death.^4,5 Another found that PARPi resistance is the loss of PARP1 DNA binding caused by mutation in the zinc finger domain of the protein by point mutation.⁵ A study investigaging Ubiquitin Ligase TRIP12 found that TRIP12 downregulation sensitized BRCA1/2 cancer cell to Olaparib by locking PARP1 in a catalytically nonproductive state.⁴ Conclusion. Research into reversion of transcriptional changes in resistant clones points to selumetinib as a promising lead for overcoming PARPi resistance in sequential combinatorial therapy.⁸ AntiCSF-1R therapy in combination with Olaparib or cotreatment with hmdU/Olaparib could be valuable therapeutic strategies^6,7, however, more research with a greater sample size and human cells would need to be investigated first before viability of these therapies can be determined.

1. Neiger HE, Siegler EL, Shi Y. Breast Cancer Predisposition Genes and Synthetic Lethality. Int J Mol Sci. 2021;22(11):5614. Published 2021 May 25.             doi:10.3390/ijms22115614
2. Lee A, Moon BI, Kim TH. BRCA1/BRCA2Pathogenic Variant Breast Cancer: Treatment and Prevention Strategies. Ann Lab Med. 2020;40(2):114-121.             doi:10.3343/alm.2020.40.2.114
3. Mahdavi M, Nassiri M, Kooshyar MM, et al. Hereditary breast cancer; Genetic penetrance and current status with BRCA. J Cell Physiol. 2019;234(5):5741-5750. doi:10.1002/jcp.27464
4. Gatti M, Imhof R, Huang Q, Baudis M, Altmeyer M. The Ubiquitin Ligase TRIP12 Limits PARP1 Trapping and Constrains PARP Inhibitor Efficiency. Cell Rep. 2020;32(5):107985. doi:10.1016/j.celrep.2020.107985
5. Pettitt SJ, Krastev DB, Brandsma I, et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun. 2018;9(1):1849. Published 2018 May 10. doi:10.1038/s41467-018-03917-2
6. Fugger K, Bajrami I, Silva Dos Santos M, et al. Targeting the nucleotide salvage factor DNPH1 sensitizes BRCA-deficient cells to PARP inhibitors. Science. 2021;372(6538):156-165. doi:10.1126/science.abb4542
7. Mehta AK, Cheney EM, Hartl CA, et al. Targeting immunosuppressive macrophages overcomes PARP inhibitor resistance in BRCA1-associated triple-negative breast cancer. Nat Cancer. 2021;2(1):66-82. doi:10.1038/s43018-020-00148-7
8. Shih DJH, Chen MK, Yin J, et al. Exploiting induced vulnerability to overcome PARPi resistance and clonal heterogeneity in BRCA mutant triple-negative inflammatory breast cancer. Am J Cancer Res. 2022;12(1):337-354. Published 2022 Jan 15.