Fig. 7: Reduced tumor progression Control with ISR-Induced NOXA Inhibition in response to PIM/MCL1 inhibitors. | Nature Communications

Fig. 7: Reduced tumor progression Control with ISR-Induced NOXA Inhibition in response to PIM/MCL1 inhibitors.

From: PIM2 inhibition promotes MCL1 dependency in plasma cells involving integrated stress response-driven NOXA expression

Fig. 7

a Serum IgK levels were monitored from treatment initiation to the endpoint at 4 weeks, normalized to baseline levels. Data are shown as mean ± SEM. Statistical comparisons were made between the AZD1208 + AZD5991 group (red, n = 5) and the AZD5991 group (blue, n = 5) on days 22 and 28, and between AZD1208 + AZD5991 with ISRIB (purple, n = 3) and without ISRIB (red, n = 4) on day 40. b Animals were considered “dead” when euthanasia was required due to various reasons. Survival was monitored throughout the experiment. c Mice were categorized based on clinical signs such as visible masses, extrafemoral tumors, limb paralysis, and general weakness. Each group was qualitatively scored. d Flow cytometry analysis of viable hCD138 + XG7 cells harvested from engrafted and control femurs and extrafemoral masses at the endpoint. e hCD138 immunostaining of engrafted and contralateral femurs from different treatment groups. The bone architecture of the femurs, particularly in the ISRIB condition, is severely altered by tumor invasion. f Unsupervised analysis revealed enriched pathways between treatment groups. Ten enriched pathways and associated genes are shown. g GSEA was conducted independently (one-sided) using two distinct signatures on the RNAseq dataset comparing AZD5991 and AZD1208 + ISRIB conditions, with analysis performed using GSEA software. h Expression levels of PMAIP1/NOXA and DDIT3/CHOP genes in tumor cells across treatment conditions, with correlation analysis. Data are mean ± SEM (n = 6). i Protein levels in tumor cells across treatment conditions were assessed by immunoblotting and protein quantification was performed using ImageJ software. Data are mean +/− SEM (n = 7). The blot is representative of 1 independent experiment. P-values were calculated using Mann-Whitney or unpaired t-tests (two-tailed) as specified for (a); Mann-Whitney test (two-tailed) for (h, left); Pearson correlation test (two-tailed) with linear regression for (h, right); and Mann-Whitney tests (two-tailed) for (i). “n”, denotes the number of distinct mouse samples. Source data are provided as a Source Data file. Two inhibitors = AZD1208 + AZD5991; IgK, immunoglobulin kappa light chain; NES, Normalized Enrichment Score; pval, nominal p-value; GSEA, Gene Set Enrichment Analysis.

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