Authors:

Kahrie Langham

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cancer cells. Inhibiting the BER pathway is an emerging strategy for the treatment of cancer, especially in breast or ovarian cancers containing mutations in the BRCA1/2 genes. Poly (ADP-Ribose) polymerase 1 (PARP1), as an integral enzyme in BER, has been targeted for the development of inhibitory drugs. Inhibiting PARP1 stops the BER pathway, resulting in the accumulation of DNA damage and eventual cell death of cancer cells. A major hurdle with PARP inhibitors (PARPi) is the development of acquired resistance. Therefore, PARPi is not often used as standalone chemotherapy and is mostly used in combination with other chemotherapeutic agents to induce a synergistic effect. By using synergy with PARPi, cancer cells will have limited time to build acquired resistance, allowing for more effective therapy. This study tested the effect of the combination inhibition of PARP and ubiquitin carboxyl-terminal hydrolase 1 (USP1), a deubiquitinase. USP1 removes ubiquitin tags from proteins that are involved in the DNA damage response, such as PCNA and FANCD2. Our specific questions were: Which type of PARPi, a PARylation inhibitor or an inhibitor that traps PARP on the DNA ("PARP trapper"), is the most effective standalone chemotherapy? Additionally, could a less effective PARPi be enhanced by inducing synthetic lethality using USP1i? The synthetic lethality of the combination treatment was tested using a cell viability assay on an ovarian cancer cell line (ES-2). The results indicate that the "PARP trapper" is the best freestanding PARPi to cause ovarian cancer cell death. While the PARylation inhibitor is less effective, ovarian cancer cell death is improved to similar levels as the "PARP trapper" by using the PARylation inhibitor in combination with USP1i. We will confirm the inhibition of PARP1 and USP1 using Immunoblot. 75 We also plan to test the combination treatment in a glioblastoma cell line (LN428) to indicate if this result is specific to ovarian cancer or used as a therapy for other cancer types. Our data will help determine which PARPi was the most effective, especially in combination with USP1i. In the future, we will test PARPi in combination with other inhibitory BER compounds to determine which pairing results in the greatest synthetic lethality. Furthermore, we hope that this research can better inform physicians about the best treatment options for their patients. Kai Capitumini:

Source:

Brown / SPRINT|Undergraduate Teaching and Research Awards (UTRA)

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Co-authors:

Kahrie Langham