Scott Mayo

Introduction. Platinu-based chemotherapy resistance has been a major challenge in BRCA deficient ovarian cancer patients.^4,5,6,7,8 BRCA deficient cancer cells have a decreased ability to repair double stranded DNA breaks. This single hit mutation is advantageous to the cancer cells, allowing for mutation to be sustained.⁵ Studies have shown that epithelial-mesenchymal transition (EMT) and the prevalence of cancer stem cells (CSC) have been closely related to the resistance seen in first line chemotherapy drugs.^4,6 As a result, Poly(ADP-ribose) Polymerase (PARP) inhibitors have been introduced as a second line therapy in ovarian cancer patients resistant to chemotherapies, with the hopes of decreasing DNA repair through synthetic lethality.^1-7,9 Despite the mechanistic promise of PARP inhibitor second line cancer therapy, it has been shown that only 2-9% of ovarian cancer patients experience complete response to PARP inhibitor monotherapy.^5,7 Methods. BRCA deficient ovarian cancer cell lines were introduced to oxidative stress with the use of H₂O₂.^2,4 Immunoblotting techniques were utilized to determine the downstream effects of PARP inhibitor monotherapy, PI3k/Akt/mTOR monotherapy, and combination therapies. Epithelial-mesenchymal transition, cancer stem cell biomarkers, and cell viability were tested. Results. Studies have shown that ovarian cancer cells evade the PARP inhibitor therapy by using a phosphorylated and inactivated ATM and binding it to NEMO (a regulatory subunit that activates NF-kB to increase inflammation).^1,10 This ATM-NEMO complex then acts as a signalosome to form a downstream complex of ATM-NEMO-Akt-mTOR complex that upregulates cell survival and proliferation, all activated and mediated by the PAPR inhibitor.^1,10 However, with the use of a combined PI3K inhibitor (BKM120) and PARP inhibitor (Olaparib), there was a synergistic suppression of ovarian cancer cell growth.² In addition, a combined PI3K/Akt/mTOR inhibitor (BEZ235) and PARP inhibitor (Cisplatin) was shown to decrease epithelial-mesenchymal transition and cancer stem cell markers in two different cell lines. This combined therapy was shown to overcome ovarian cancer cell chemoresistance.⁴ Conclusions. PARP inhibitors induced inactivation of ATM DNA repair enzymes that activated a downstream ATM/NEMO/PI3K/Akt/mTOR signalosome that upregulates cancer cell survival and proliferation even in the presence of therapy.^1-5 A novel combined PARP inhibitor and PI3K/Akt inhibitor therapy has shown to decrease EMT and CSC levels and increase the synthetic lethality success in BRCA deficient ovarian cancer cells.^1-5

1. Tapodi A, Bognar Z, Szabo C, Gallyas F, Sumegi B, Hocsak E. PARP inhibition induces Akt-mediated cytoprotective effects through the formation of a mitochondria-targeted phospho-ATM-NEMO-Akt-mTOR signalosome. Biochem Pharmacol. 2019;162:98-108. doi:10.1016/j.bcp.2018.10.005
2. Wang D, Li C, Zhang Y, et al. Combined inhibition of PI3K and PARP is effective in the treatment of ovarian cancer cells with wild-type PIK3CA genes. Gynecol Oncol. 2016;142(3):548-556. doi:10.1016/j.ygyno.2016.07.092
3. Yap, Timothy A., et al. “Phase I Trial of the PARP Inhibitor Olaparib and AKT Inhibitor Capivasertib in Patients with BRCA1/2- and Non–BRCA1/2-Mutant Cancers.” Cancer Discovery, vol. 10, no. 10, 2020, pp. 1528–1543., doi:10.1158/2159-8290.cd-20-0163.
4. Deng J, Bai X, Feng X, et al. Inhibition of PI3K/Akt/mTOR signaling pathway alleviates ovarian cancer chemoresistance through reversing epithelial-mesenchymal transition and decreasing cancer stem cell marker expression. BMC Cancer. 2019;19(1):618. Published 2019 Jun 24. doi:10.1186/s12885-019-5824-9
5. Kim, H., Xu, H., George, E. et al. Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun 11, 3726 (2020). https://doi.org/10.1038/s41467-020-17127-2
6. Li H, Liu ZY, Wu N, Chen YC, Cheng Q, Wang J. PARP inhibitor resistance: the underlying mechanisms and clinical implications. Mol Cancer. 2020;19(1):107. Published 2020 Jun 20. doi:10.1186/s12943-020-01227-0
7. Xie H, Wang W, Xia B, Jin W, Lou G. Therapeutic applications of PARP inhibitors in ovarian cancer. Biomed Pharmacother. 2020;127:110204. doi:10.1016/j.biopha.2020.110204
8. Lee EK, Matulonis UA. Emerging drugs for the treatment of ovarian cancer: a focused review of PARP inhibitors. Expert Opin Emerg Drugs. 2020;25(2):165-188. doi:10.1080/14728214.2020.1773791
9. Gallyas F Jr, Sumegi B, Szabo C. Role of Akt Activation in PARP Inhibitor Resistance in Cancer. Cancers (Basel). 2020;12(3):532. Published 2020 Feb 25. doi:10.3390/cancers12030532
10. Tapodi A, Bognar Z, Szabo C, Gallyas F, Sumegi B, Hocsak E. PARP inhibition induces Akt-mediated cytoprotective effects through the formation of a mitochondria-targeted phospho-ATM-NEMO-Akt-mTOR signalosome. Biochem Pharmacol. 2019;162:98-108. doi:10.1016/j.bcp.2018.10.005