Background
Inhibitors of Poly (ADP-Ribose) Polymerases (PARP) provide clinical benefit to patients with breast and ovarian cancers, by compromising the DNA repair activity of cancer cells. Although these agents extend progression-free survival in many patients, responses can be short lived with many patients ultimately progressing. Identification of combination partners that increase dependence of cancer cells to the DNA repair activity of PARPs may represent a strategy to increase the utility of PARP inhibitors. Protein arginine methyltransferase 5 (PRMT5) regulates DNA damage response pathways through splicing and protein modification, and inhibitors of PRMT5 have recently entered clinical trials.
Conclusion
These data demonstrate that inhibition of PRMT5 induced signatures of DNA damage in models of breast and ovarian cancer. Furthermore, combination with the PARP inhibitor, Niraparib, resulted in increased anti-tumor activity in vitro and in vivo. Overall, these data suggest inhibition of PRMT5 as a mechanism to broaden and enhance the clinical application of PARP inhibitors.
Methods
The effect of PRMT5 inhibition on the levels of DNA damage and repair markers including γH2AX, RAD51, and 53BP1 was determined using high content immunofluorescent imaging. The anti-proliferative activity of the combination of PRMT5 and PARP inhibitors was evaluated using in vitro models of breast and ovarian cancers using both cell lines and ex vivo patient derived xenografts. Finally, the combinations of PRMT5 and PARP inhibitors were evaluated in cell line xenograft models in vivo.
Results
Inhibition of PRMT5 by GSK3326595 led to increased levels of markers of DNA damage. The addition of GSK3326595 to the PARP inhibitor, niraparib, resulted in increased growth inhibition of breast and ovarian cancer cell lines and patient derived spheroids. In vivo, the combination improved the partial effects on tumor growth inhibition achieved by either single agent, producing complete tumor stasis and regression.