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. 2022 Nov 30;12:1021632. doi: 10.3389/fonc.2022.1021632

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Copyright © 2022 Prasopporn, Suppramote, Ponvilawan, Jamyuang, Chanthercrob, Chaiboonchoe, More-Krong, Kongsri, Suntiparpluacha, Chanwat, Korphaisarn, Okada, Sampattavanich and Jirawatnotai

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Anti-cancer effect of triplet LCL161 + GEM/CIS therapy in CCA PDOs. (A) Dose-response curves for LCL161, GEM/CIS, or LCL161 + GEM/CIS in a primary CCA cell line SiK03. (B, C) Dose-response curves for LCL161, GEM/CIS, or LCL161 + GEM/CIS in two models of PDOs (Si_003 and NCI_001). The lines represent the averages of triplicate data ± SD. The PDOs were treated for 5 days, the GR₅₀ values were obtained, and (D) the morphologies of Si_003 PDOs treated with indicated therapies were visualized. (E) The 5-day GR₅₀ values for LCL161, GEM/CIS, and LCL161 + GEM/CIS in PDOs. (F) Horizontal flow diagram describing our findings. Under GEM/CIS treatment, CCA cells adapted in an effort to survive the drug treatment by upregulating cIAP2, which resulted in a newly acquired vulnerability to SMAC mimetics, such as LCL161. Combining SMAC mimetics with the standard GEM/CIS treatment regimen was shown to promote synergistic inhibition of multidrug-resistant CCA.