Figure - PMC

Skip to main content

An official website of the United States government

Here's how you know

Here's how you know

Official websites use .gov
A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS
A lock ( ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

View full-text article in PMC

. 2023 Sep 7;4(9):1362–1381. doi: 10.1038/s43018-023-00628-6

Search in PMC
Search in PubMed
View in NLM Catalog
Add to search

© The Author(s) 2023

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

PMC Copyright notice

Fig. 8 — a, Irinotecan is converted to the active metabolite SN-38 in liver and small intestinal epithelial cells and also pancreatic cancer cells. CYP3A proteins may metabolize irinotecan into inactive metabolites APC and NPC, leading to drug tolerance. SN-38 may also undergo glucuronidation and be exported from cancer cells. CYP3A inhibitors, such as ketoconazole and cobicistat, may overcome irinotecan drug tolerance by increasing the accumulation of SN-38. b, Compound analysis by UPLC–MS/MS of irinotecan metabolites in relative resistant (n = 3) and relative susceptible (n = 3) PDOs showing intracellular irinotecan-to-SN-38 conversion (left) and SN-38 accumulation in the supernatant (right). Biological replicates (n = 3) for the representative PDOs are shown in the plots. Wilcoxon rank-sum test two-sided P values are shown on the plots. P values were not adjusted for multiple testing. c, Compound analysis by UPLC–MS/MS of relative resistant and relative susceptible PDOs showing the accumulation of SN-38 or inactive metabolite APC in the supernatant following irinotecan treatment. The results represent n = 3 independent biological experiments. Data are presented as mean ± s.d. One-way analysis of variance (two-tailed) P values are shown on the plots. P values were not adjusted for multiple testing. d, Treatment of an irinotecan-resistant PDO (h20) with irinotecan, paclitaxel and SN-38 in combination with either ketoconazole or cobicistat as indicated. Combination treatment with ketoconazole increases drug sensitivity to irinotecan and paclitaxel but not SN-38. The results represent n = 3 independent biological experiments. Data are presented as mean ± s.e.m. IC₅₀ values are provided for the indicated treatments. e, Alternative models to explain drug tolerance and persistence in post-CTX samples. Intrinsic resistance: treatment-mediated selection of preexisting drug-tolerant phenotypes may shape residual disease. This process may involve non-genetic mechanisms, including intrinsic and/or drug-induced expression of drug-detoxifying genes and/or a transition toward basal-like or ‘hybrid’ states from predominant classical states due to intrinsic neoplastic plasticity. Acquired resistance: rare subclones acquire a drug-resistant driver alteration before or during therapy. These resistant clones expand and eventually drive relapse due the clonal acquisition of the preexisting drug-resistant mechanism.

Source data