The following is a summary of “JQ-1/bortezomib combination strongly impairs MM and PEL survival by inhibiting c-Myc and mTOR despite the activation of prosurvival mechanisms,” published in April 2023 issue of Experimental Hematology by Arena et al. 

Multiple Myeloma (MM) and Primary Effusion Lymphoma (PEL) are highly aggressive hematologic malignancies that have shown some degree of success in response to Bortezomib and JQ-1. Bortezomib is a proteasome inhibitor, while JQ-1 is a bromodomain and extra terminal domain (BET) inhibitor. The synergistic effect of combined therapy holds more significant potential than monotherapy in treating various malignancies, including multiple myeloma. In the latter case, inhibition of proteasome resulted in the upregulation of nuclear respiratory factor 1 (NRF1), which exhibited a prosurvival effect. However, this effect was counteracted by BET inhibitors. The study reveals that the combination of JQ-1 and bortezomib has a potent cytotoxic effect on PEL. Furthermore, the study provides novel insights into the mechanisms underlying the cytotoxic effects of this drug combination on both PEL and MM cells. 

The cells exhibited a heightened reduction of c-Myc, resulting in amplified DNA damage, specifically upon administration of JQ-1/bortezomib compared to individual drug treatment. The observed impact resulted from inhibiting the mechanistic target of rapamycin (mTOR) – phosphorylated eukaryotic translation initiation factor 4E – binding protein 1 (p-4EBP1) axis, which was facilitated by the downregulation of c-Myc. In addition to its pro-death effects, the administration of JQ-1/bortezomib has been observed to induce the activation of unfolded protein response (UPR) and autophagy as mechanisms that promote cell survival. 

The findings of this study indicate that the combination of JQ-1 and bortezomib may have the potential as a treatment for multiple myeloma (MM) and primary effusion lymphoma (PEL). The study also revealed novel molecular mechanisms underlying the cytotoxic effects of this combination therapy. Furthermore, the study suggests that inhibiting the unfolded protein response (UPR) and autophagy may enhance the cytotoxicity of JQ-1/bortezomib.

Source: sciencedirect.com/science/article/abs/pii/S0301472X23000012