Figure 4: TRIB2-conferred resistance to PI3K inhibitors in vivo and ex vivo and correlates with poor clinical prognosis. | Nature Communications

Figure 4: TRIB2-conferred resistance to PI3K inhibitors in vivo and ex vivo and correlates with poor clinical prognosis.

From: RETRACTED ARTICLE: TRIB2 confers resistance to anti-cancer therapy by activating the serine/threonine protein kinase AKT

Figure 4

(a) Kaplan–Meier analysis of isogenic TRIB2 cell lines grow subcutaneously in NOD/Scid mice treated with vehicle (n=7), of BEZ235 (n=7). The presence of TRIB2 significantly reduced survival (log rank P=0.033) when treated daily with BEZ235. (b) TRIB2 overexpressing 293T tumours (n=7) show little to no response to daily administration of BEZ235 compared to isogenic lines with endogenous (low, n=7) TRIB2 expression. (c) Representative immunoblot analysis of key proteins of interest from in vivo treated tumours. Only three tumours were present from the 293T-empty-BEZ235 treatment group. Red line (on 293-TRIB2 treated immunoblots highlight bands from the same membrane that were spliced due to lane gaps left on the original full immunoblot. Original full membranes are provided in Supplementary Information; Supplementary Fig. 19). (d) (left panel) Quantitative real time PCR (qRT-PCR) analysis of gene expression in ex vivo metastatic melanoma samples (n=20) versus normal control tissue (n=10). Data were analysed by two-way ANOVA) and values represent the mean±s.d. (right panel), Quantitative real time PCR (qRT-PCR) analysis of gene expression in ex vivo metastatic melanoma samples (n=20) versus normal control tissue (n=10) classified by clinical response to first line chemotherapy (complete response n=5, stable disease n=5 or progressive disease n=10). Data were analysed by two-way ANOVA) *P≤0.05, **P≤0.01, ***P≤0.001) and values represent the mean±s.d. (e) Representative immunoblot analysis of the AKT signalling cascade from ex vivo metastatic melanoma samples compared to normal tissue samples. (f) Representative immunofluorecent images of metastatic melanoma dual stained for TRIB2 and pSer473-AKT1 demonstrating co-staining and interaction. (g) Kaplan–Meier analysis from melanoma patients in the GSE65904 dataset classified based on low (≥1.5 fold) or high (≥2.5 fold) TRIB2 expression. Log-rank tests reveal that TRIB2 expression is highly significant for patient prognosis with median survival for low (4,450 days) and high (394 days) expression respectively. (h) Kaplan–Meier analysis for metastasis-free survival based on low (≥1.5 fold) or high (≥2.5 fold) TRIB2 expression (i) Proposed model of TRIB2-mediated drug resistance.

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