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Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma

Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest o...

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Autores principales: Prasopporn, Sunisa, Suppramote, Orawan, Ponvilawan, Ben, Jamyuang, Chanette, Chanthercrob, Jantappapa, Chaiboonchoe, Amphun, More-Krong, Pimkanya, Kongsri, Kamonchanok, Suntiparpluacha, Monthira, Chanwat, Rawisak, Korphaisarn, Krittiya, Okada, Seiji, Sampattavanich, Somponnat, Jirawatnotai, Siwanon
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748615/
https://www.ncbi.nlm.nih.gov/pubmed/36531039
http://dx.doi.org/10.3389/fonc.2022.1021632
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author Prasopporn, Sunisa
Suppramote, Orawan
Ponvilawan, Ben
Jamyuang, Chanette
Chanthercrob, Jantappapa
Chaiboonchoe, Amphun
More-Krong, Pimkanya
Kongsri, Kamonchanok
Suntiparpluacha, Monthira
Chanwat, Rawisak
Korphaisarn, Krittiya
Okada, Seiji
Sampattavanich, Somponnat
Jirawatnotai, Siwanon
author_facet Prasopporn, Sunisa
Suppramote, Orawan
Ponvilawan, Ben
Jamyuang, Chanette
Chanthercrob, Jantappapa
Chaiboonchoe, Amphun
More-Krong, Pimkanya
Kongsri, Kamonchanok
Suntiparpluacha, Monthira
Chanwat, Rawisak
Korphaisarn, Krittiya
Okada, Seiji
Sampattavanich, Somponnat
Jirawatnotai, Siwanon
author_sort Prasopporn, Sunisa
collection PubMed
description Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required. To that end – in this study, we developed several acquired GEM/CIS-resistant CCA cell lines and we screened those cell lines for acquired vulnerability. The screening process revealed that subset of CCA with GEM/CIS resistance acquired vulnerability to the small-molecule second mitochondrial-derived activator of caspases (SMAC) mimetics LCL161 and Birinapant. The observed acquired vulnerability was found to be associated with upregulation of an inhibitor of apoptosis protein 2 (cIAP2), a known target of SMAC mimetics. LCL161 or cIAP2-shRNA downregulated cIAP2 and restored the sensitivity to GEM/CIS in GEM/CIS-resistant CCA cell lines and in in vivo GEM/CIS-resistant xenograft models. A strong synergic effect was observed when LCL161 was added to GEM/CIS. Interestingly, this synergism was also observed in drug-naïve CCA cell lines, xenografts, and patient-derived organoids. This triplet therapy also prevented the emergence of multidrug-resistant CCA in in vitro and in vivo models. Our findings suggest that activation of cIAP2 allows CCA to escape GEM/CIS, and that suppression of cIAP2 reestablishes the apoptotic profile of CCA, thus restoring its vulnerability to GEM/CIS. The results of this study indicate that combining the SMAC mimetic LCL161 with GEM/CIS inhibits and prevents the emergence of multidrug resistance in CCA.
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spelling pubmed-97486152022-12-15 Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma Prasopporn, Sunisa Suppramote, Orawan Ponvilawan, Ben Jamyuang, Chanette Chanthercrob, Jantappapa Chaiboonchoe, Amphun More-Krong, Pimkanya Kongsri, Kamonchanok Suntiparpluacha, Monthira Chanwat, Rawisak Korphaisarn, Krittiya Okada, Seiji Sampattavanich, Somponnat Jirawatnotai, Siwanon Front Oncol Oncology Cholangiocarcinoma (CCA) is a highly lethal gastrointestinal malignancy that has one of the worst prognoses among solid tumors. The combination of Gemcitabine + Cisplatin (GEM/CIS) remains the standard first-line treatment for advanced stage CCA. However, this drug combination yields only a modest objective response rate, and in cases that initially respond to this treatment, drug resistance commonly rapidly develops. To improve the efficiency of GEM/CIS therapy for CCA, a thorough understanding of the mechanism of GEM/CIS resistance in CCA is required. To that end – in this study, we developed several acquired GEM/CIS-resistant CCA cell lines and we screened those cell lines for acquired vulnerability. The screening process revealed that subset of CCA with GEM/CIS resistance acquired vulnerability to the small-molecule second mitochondrial-derived activator of caspases (SMAC) mimetics LCL161 and Birinapant. The observed acquired vulnerability was found to be associated with upregulation of an inhibitor of apoptosis protein 2 (cIAP2), a known target of SMAC mimetics. LCL161 or cIAP2-shRNA downregulated cIAP2 and restored the sensitivity to GEM/CIS in GEM/CIS-resistant CCA cell lines and in in vivo GEM/CIS-resistant xenograft models. A strong synergic effect was observed when LCL161 was added to GEM/CIS. Interestingly, this synergism was also observed in drug-naïve CCA cell lines, xenografts, and patient-derived organoids. This triplet therapy also prevented the emergence of multidrug-resistant CCA in in vitro and in vivo models. Our findings suggest that activation of cIAP2 allows CCA to escape GEM/CIS, and that suppression of cIAP2 reestablishes the apoptotic profile of CCA, thus restoring its vulnerability to GEM/CIS. The results of this study indicate that combining the SMAC mimetic LCL161 with GEM/CIS inhibits and prevents the emergence of multidrug resistance in CCA. Frontiers Media S.A. 2022-11-30 /pmc/articles/PMC9748615/ /pubmed/36531039 http://dx.doi.org/10.3389/fonc.2022.1021632 Text en Copyright © 2022 Prasopporn, Suppramote, Ponvilawan, Jamyuang, Chanthercrob, Chaiboonchoe, More-Krong, Kongsri, Suntiparpluacha, Chanwat, Korphaisarn, Okada, Sampattavanich and Jirawatnotai https://creativecommons.org/licenses/by/4.0/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.
spellingShingle Oncology
Prasopporn, Sunisa
Suppramote, Orawan
Ponvilawan, Ben
Jamyuang, Chanette
Chanthercrob, Jantappapa
Chaiboonchoe, Amphun
More-Krong, Pimkanya
Kongsri, Kamonchanok
Suntiparpluacha, Monthira
Chanwat, Rawisak
Korphaisarn, Krittiya
Okada, Seiji
Sampattavanich, Somponnat
Jirawatnotai, Siwanon
Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
title Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
title_full Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
title_fullStr Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
title_full_unstemmed Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
title_short Combining the SMAC mimetic LCL161 with Gemcitabine plus Cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
title_sort combining the smac mimetic lcl161 with gemcitabine plus cisplatin therapy inhibits and prevents the emergence of multidrug resistance in cholangiocarcinoma
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9748615/
https://www.ncbi.nlm.nih.gov/pubmed/36531039
http://dx.doi.org/10.3389/fonc.2022.1021632
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