Scott Mayo

 Introduction. Platinum-based chemotherapy resistance has been a major challenge in BRCA deficient ovarian cancer patients.^1,2,3,4,5 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.^1,3 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.^1-9 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.^2,4 Methods. Oxidative stress was induced in BRCA deficient ovarian cancer cell lines by treatment with H₂O₂.^1,6 Immunoblotting techniques were utilized to determine the downstream effects of PARP inhibitor monotherapy, PI3k/Akt/mTOR monotherapy, and combination therapies. EMT, 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).⁹ This ATM-NEMO complex then acts as a signalosome to form a downstream complex of an ATM-NEMO-Akt-mTOR complex that upregulates cell survival and proliferation, all activated and mediated by the PAPR inhibitor.⁹ However, with the use of a combined PI3K inhibitor (BKM120) and PARP inhibitor (Olaparib), there was a synergistic suppression of ovarian cancer cell growth.⁶  In addition, a combined PI3K/Akt/mTOR inhibitor (BEZ235) and PARP inhibitor (Cisplatin) was shown to decrease EMT and cancer stem cell markers in two different cell lines. This combined therapy was shown to overcome ovarian cancer cell chemoresistance.^6-9 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.^6-9 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.^6-9

1. 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
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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.
8. 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
9. 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