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Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations

Liver kinase B1 (LKB1/STK11) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerab...

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Autores principales: Colombo, Marika, Marabese, Mirko, Vargiu, Giulia, Broggini, Massimo, Caiola, Elisa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643013/
https://www.ncbi.nlm.nih.gov/pubmed/33194590
http://dx.doi.org/10.3389/fonc.2020.532292
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author Colombo, Marika
Marabese, Mirko
Vargiu, Giulia
Broggini, Massimo
Caiola, Elisa
author_facet Colombo, Marika
Marabese, Mirko
Vargiu, Giulia
Broggini, Massimo
Caiola, Elisa
author_sort Colombo, Marika
collection PubMed
description Liver kinase B1 (LKB1/STK11) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerabilities of this subgroup of tumors exploitable to design specific therapies we screened an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1. Among eight hit compounds, Birinapant, an inhibitor of the Inhibitor of Apoptosis Proteins (IAPs), was the most active compound in LKB1-deleted clone only compared to its LKB1 WT counterpart. We validated the Birinapant cells response and its mechanism of action to be dependent on LKB1 deletion. Indeed, we demonstrated the ability of this compound to induce apoptosis, through activation of caspases in the LKB1-deleted clone only. Expanding our results, we found that the presence of KRAS mutations could mediate Birinapant resistance in a panel of NSCLC cell lines. The combination of Birinapant with Ralimetinib, inhibitor of p38α, restores the sensitivity of LKB1- and KRAS-mutated cell lines to the IAP inhibitor Birinapant. Our study shows how the use of Birinapant could be a viable therapeutic option for patients with LKB1-mutated NSCLCs. In addition, combination of Birinapant and a KRAS pathway inhibitor, as Ralimetinib, could be useful for patients with LKB1 and KRAS-mutated NSCLC.
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spelling pubmed-76430132020-11-13 Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations Colombo, Marika Marabese, Mirko Vargiu, Giulia Broggini, Massimo Caiola, Elisa Front Oncol Oncology Liver kinase B1 (LKB1/STK11) is the second tumor suppressor gene most frequently mutated in non-small-cell lung cancer (NSCLC) and its activity is impaired in about half KRAS-mutated NSCLCs. Nowadays, no effective therapies are available for patients having these mutations. To highlight new vulnerabilities of this subgroup of tumors exploitable to design specific therapies we screened an US FDA-approved drug library using an isogenic system of wild-type (WT) or deleted LKB1. Among eight hit compounds, Birinapant, an inhibitor of the Inhibitor of Apoptosis Proteins (IAPs), was the most active compound in LKB1-deleted clone only compared to its LKB1 WT counterpart. We validated the Birinapant cells response and its mechanism of action to be dependent on LKB1 deletion. Indeed, we demonstrated the ability of this compound to induce apoptosis, through activation of caspases in the LKB1-deleted clone only. Expanding our results, we found that the presence of KRAS mutations could mediate Birinapant resistance in a panel of NSCLC cell lines. The combination of Birinapant with Ralimetinib, inhibitor of p38α, restores the sensitivity of LKB1- and KRAS-mutated cell lines to the IAP inhibitor Birinapant. Our study shows how the use of Birinapant could be a viable therapeutic option for patients with LKB1-mutated NSCLCs. In addition, combination of Birinapant and a KRAS pathway inhibitor, as Ralimetinib, could be useful for patients with LKB1 and KRAS-mutated NSCLC. Frontiers Media S.A. 2020-10-22 /pmc/articles/PMC7643013/ /pubmed/33194590 http://dx.doi.org/10.3389/fonc.2020.532292 Text en Copyright © 2020 Colombo, Marabese, Vargiu, Broggini and Caiola http://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
Colombo, Marika
Marabese, Mirko
Vargiu, Giulia
Broggini, Massimo
Caiola, Elisa
Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations
title Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations
title_full Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations
title_fullStr Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations
title_full_unstemmed Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations
title_short Activity of Birinapant, a SMAC Mimetic Compound, Alone or in Combination in NSCLCs With Different Mutations
title_sort activity of birinapant, a smac mimetic compound, alone or in combination in nsclcs with different mutations
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643013/
https://www.ncbi.nlm.nih.gov/pubmed/33194590
http://dx.doi.org/10.3389/fonc.2020.532292
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