Concomitant Inhibition of IRE1α/XBP1 Axis of UPR and PARP: A Promising Therapeutic Approach against c-Myc and Gammaherpesvirus-Driven B-Cell Lymphomas
- Int J Mol Sci. 2022 Aug 14;23(16):9113. doi: 10.3390/ijms23169113.
- 1. Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy.
It is emerging that targeting the adaptive functions of Unfolded Protein Response (UPR) may represent a promising anti-cancer therapeutic approach. This is particularly relevant for B-cell lymphomas, characterized by a high level of constitutive stress due to high c-Myc expression. In this study, we found that IRE1α/XBP1 axis inhibition exerted a stronger cytotoxic effect compared to the inhibition of the Other two UPR sensors, namely PERK and ATF6, in Burkitt lymphoma (BL) cells, in correlation with c-Myc downregulation. Interestingly, such an effect was more evident in Epstein-Barr virus (EBV)-negative BL cells or those cells expressing type I latency compared to type III latency BL cells. The Other interesting finding of this study was that the inhibition of IRE1α/XBP1 downregulated BRCA-1 and RAD51 and potentiated the cytotoxicity of PARP Inhibitor AZD2661 against BL cells and also against Primary Effusion Lymphoma (PEL), another aggressive B-cell lymphoma driven by c-Myc and associated with gammaherpesvirus Infection. These results suggest that combining the inhibition of UPR sensors, particularly IRE1α/XBP1 axis, and molecules involved in DDR, such as PARP, could offer a new therapeutic opportunity for treating aggressive B-cell lymphomas such as BL and PEL.