Uncovering the Role of PIM2 in Modulating MCL1 Dependency and Activation of ISR-Mediated NOXA Expression

Our study delves into the intricate dynamics of the integrated stress response (ISR) axis, focusing on the pivotal role of PIM2 kinase and its interaction with the BCL2 family of proteins, revealing crucial mechanisms governing cell survival and tumor progression. Elevated PIM2 expression is a hallmark of various cancers, often correlating with disease aggressiveness. Using a model of normal and malignant plasma cells, we unveil that inhibiting PIM2 kinase triggers not only the production of phosphorylated BAD but also activates ISR-mediated NOXA expression. This shift towards heightened dependence on MCL1 underscores the synergy achieved through combined PIM/MCL1 inhibition, largely propelled by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth, a response reversed by ISR-specific inhibition, concomitant with the upregulation of genes associated with tumor cell dissemination. These findings illuminate the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, particularly in tumors marked by elevated PIM2 expression. To investigate the contribution of the ISR pathway for the synergy of the combinaison of AZD1208 and AZD5991 in a xenograft model of XG7 human MM cell line, we treated mice (receiving the combinaison) with the molecule ISRIB. At mice sacrifice, human tumoral cells were sorted and we performed gene analysis profiling using data obtained from RNAseq of 12 tumoral samples from 12 differents mice receiving the combinaison AZD1208 and AZD5991 and grouped in 2 groups whose one (6 mice/samples) were treated with ISRIB (tested group) and the other (6 mice/samples) are not treated with ISRIB (control group). Comparative gene analysis profiling of the RNAseq data was performed in human tumor cells sample control group and the tested group.