Fig. 6: JOSD2 catalytic inhibitor HY041004 preferentially impedes KRAS-mutant CRC growth in vitro/in vivo. | Nature Communications

Fig. 6: JOSD2 catalytic inhibitor HY041004 preferentially impedes KRAS-mutant CRC growth in vitro/in vivo.

From: Josephin Domain Containing 2 (JOSD2) inhibition as Pan-KRAS-mutation-targeting strategy for colorectal cancer

Fig. 6

a HY041004 reversed the effects of JOSD2 deubiquitinating KRAS mutants. b HY041004 downregulated KRAS mutants’ protein levels in a concentration-dependent manner. c HY041004 inhibited the cell proliferation of KRAS-mutant CRC cells in vitro. WT, wild-type; Mut, mutation. (means ± SD, n = 3; three independent experiments were performed). d HY041004 inhibited the colony formation of KRAS-mutant CRC cells in a concentration-dependent manner in vitro. SW480/SW620 cells were treated with the indicated concentration of HY041004 for 72 h (SW480: 0, 0.03, 0.06, 0.12 μM; SW620: 0, 0.06, 0.09, 0.12 μM), then replaced with fresh medium and cultured for another 14 days followed by colony formation assays; Scale bar, 5 mm. e The inhibitory effects of HY041004 on the cells proliferation of KRAS-mutant cells are stronger than KRAS wild-type cells in vitro. P, vs. KRAS-WT. (means ± SD, n = 3; three independent experiments were performed). f The inhibitory effects of HY041004 on the colony formation of KRAS-mutant cells are stronger than KRAS wild-type cells in vitro; Scale bar, 5 mm. g–i HY041004 posed more potent anti-tumor effects on KRAS-mutant xenografts compared to KRAS wild-type in vivo (means ± S.E.M., n = 7 mice/group). g The tumor volume of the indicated groups. h The tumor weight of the indicated groups. i HY041004 downregulated intratumor KRAS levels of KRAS-mutant xenografts stronger than those of KRAS wild-type xenografts. j The represent images of CRC PDO. Scale bar, 200 μm. k HY041004 significantly downregulated KRAS levels in PDOs (patient-derived organoids). CRC, colorectal cancer; Scale bar, 100 μm. l HY041004 posed more potent anti-tumor activity on KRAS-mutant CRC PDO in vitro. (means ± SD, n = 3; three independent experiments were performed). The significance analysis of (e, g, h) was conducted by One-way ANOVA (Bonferroni method was utilized to correct for multiple comparisons), and (i, l) was conducted by Two-tailed unpaired Student’s t-tests. Source data are provided as a Source Data file.

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