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. 2022 Nov;42(11):1212-1216.
doi: 10.1002/cac2.12365. Epub 2022 Sep 30.

Inhibition of glucuronidation in pancreatic cancer improves gemcitabine anticancer activity

Nicolas Alejandro Fraunhoffer  1   2 , Analía Meilerman Abuelafia  1 , Brice Chanez  1 , Martin Bigonnet  1   3 , Odile Gayet  1 , Julie Roques  1 , Eduardo Chuluyan  2   4 , Nelson Dusetti  1 , Juan Iovanna  1
Affiliations

Inhibition of glucuronidation in pancreatic cancer improves gemcitabine anticancer activity

Nicolas Alejandro Fraunhoffer et al. Cancer Commun (Lond). 2022 Nov.
No abstract available

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Figures

FIGURE 1
FIGURE 1
Derivation and validation of a gemcitabine‐response component. (A). PDX and PDC agglomerative hierarchical clustering of transcriptomic data unravel 7 patients with high transcriptomic similarity (HTS, PDAC028T, PDAC031T, PDAC054T, PDAC083T, PDAC087T, PDAC089T and PDAC091T). (B) Boxplot of Spearman correlation coefficients shows a high correlation between PDXs and the corresponding PDCs in the HTS patients (0.48 ± 0.11) compared with the low transcriptomic similarity group (LTS, n = 31), which displayed a coefficient of 0.13 ± 0.18 (P < 0.001). (C) Identification of ICA2 component as gemcitabine‐response component by independent component analysis on the 7 HTS PDCs and Spearman correlation with the AUC as selection parameter (r = −0.93, P = 0.003). (D) ICA2 sample contribution correlates positively with the ICA4 component extracted from the 7 HTS PDXs (r = 0.93, P = 0.003). (E) Scatterplots representing the correlation between the projected ICA2 and the response to gemcitabine measured by AUC, with Spearman test in an independent cohort of 31 PDCs (r = −0.43, P = 0.010), 13 PDXs (r = −0.63, P = 0.010), 14 PDOs (r = −0.70, P = 0.003) and 11 CCLs (r = −0.61, P = 0.027). (F) Nicole et al., cohort (n = 305) showed a significant patient stratification following the GemCore signature for disease‐free survival (DFS). GemCore+ patients treated with gemcitabine showed a median DSF (38.6 months, 95% CI = 19.93‐Not reached) higher than other groups (G) Nicolle et al. cohort GemCore+ patients treated with gemcitabine showed a DFS hazard ratio of 0.5 (95% CI = 0.32‐0.79, P = 0.003). (H) GemCore pathway enrichment analysis shows an association between drug detoxification mechanisms, such as glucuronidation (FDR < 0.001), phase II conjugation of compounds (FDR < 0.001), and biological oxidations (FDR < 0.001) with gemcitabine resistance. (I) GemCore String enrichment analysis shows significant protein‐protein interactions (PPI) between the UGT proteins (J) The IC50 after the treatment with diclofenac, observing a significant reduction in the IC50 in the resistant PDCs at 25 μmol/L. (K) UGT1A expression measured by immunofluorescence in a set of PDX samples distributed along the gemcitabine response profile, displaying a range from 85% to no detectable number of cells. Scale bar: 200 μm. (L) Spearman correlation of UGT activity and percentage of resistance in a set of fifteen PDXs (r = 0.79, P < 0.001). (M) Tumor growth curves for six PDXs (3 resistant and 3 sensitive) treated with vehicle, gemcitabine, diclofenac, or diclofenac plus gemcitabine. Resistant PDXs (PDAC076T, PDAC082T, and PDAC085T) treated with diclofenac and gemcitabine show a significant reduction in tumor volume compared with gemcitabine alone. (N) Box plot of UGT activity levels in resistant PDXs at the end time‐point. *P < 0.05; **P < 0.01; ***P < 0.001. Results are shown as means ± SD. Differences between two groups are calculated by the Mann‐Whitney test. Multi‐group comparison is calculated by the Kruskal‐Wallis test following Dunn's test
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References

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