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BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response

Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the differential response to chemotherapy observed in the clinic. BH3 mimetics, which target anti-apoptotic BCL-2 family members, have shown potential in the treatment of hematological malignancies and offer promise for the t...

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Autores principales: Zhang, Le, Ramesh, Prashanthi, Steinmetz, Maxime, Medema, Jan Paul
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067732/
https://www.ncbi.nlm.nih.gov/pubmed/33917026
http://dx.doi.org/10.3390/ijms22083811
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author Zhang, Le
Ramesh, Prashanthi
Steinmetz, Maxime
Medema, Jan Paul
author_facet Zhang, Le
Ramesh, Prashanthi
Steinmetz, Maxime
Medema, Jan Paul
author_sort Zhang, Le
collection PubMed
description Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the differential response to chemotherapy observed in the clinic. BH3 mimetics, which target anti-apoptotic BCL-2 family members, have shown potential in the treatment of hematological malignancies and offer promise for the treatment of solid tumors as well. To gain a comprehensive understanding of the response to BH3 mimetics in CRC and the underlying molecular factors predicting sensitivity, we screened a panel of CRC cell lines with four BH3 mimetics targeting distinct anti-apoptotic BCL-2 proteins. Treatment with compounds alone and in combination revealed potent efficacy of combined MCL-1 and BCL-XL inhibition in inducing CRC cell death, irrespective of molecular features. Importantly, expression of the anti-apoptotic protein target of BH3 mimetics on its own did not predict sensitivity. However, the analysis did identify consensus molecular subtype (CMS) specific response patterns, such as higher resistance to single and combined BCL-2 and MCL-1 inhibition in CMS2 cell lines. Furthermore, analysis of mutation status revealed that KRAS mutant cell lines were more resistant to MCL-1 inhibition. Conclusively, we find that CRC cell lines presented with distinct responses to BH3 mimetics that can in part be predicted by their CMS profile and KRAS/BRAF mutations. Overall, almost all CRC lines share sensitivity in the nanomolar range to combined MCL-1 and BCL-XL targeting suggesting that this would be the preferred approach to target these cancers.
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spelling pubmed-80677322021-04-25 BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response Zhang, Le Ramesh, Prashanthi Steinmetz, Maxime Medema, Jan Paul Int J Mol Sci Article Colorectal cancer (CRC) is a heterogeneous disease, which in part explains the differential response to chemotherapy observed in the clinic. BH3 mimetics, which target anti-apoptotic BCL-2 family members, have shown potential in the treatment of hematological malignancies and offer promise for the treatment of solid tumors as well. To gain a comprehensive understanding of the response to BH3 mimetics in CRC and the underlying molecular factors predicting sensitivity, we screened a panel of CRC cell lines with four BH3 mimetics targeting distinct anti-apoptotic BCL-2 proteins. Treatment with compounds alone and in combination revealed potent efficacy of combined MCL-1 and BCL-XL inhibition in inducing CRC cell death, irrespective of molecular features. Importantly, expression of the anti-apoptotic protein target of BH3 mimetics on its own did not predict sensitivity. However, the analysis did identify consensus molecular subtype (CMS) specific response patterns, such as higher resistance to single and combined BCL-2 and MCL-1 inhibition in CMS2 cell lines. Furthermore, analysis of mutation status revealed that KRAS mutant cell lines were more resistant to MCL-1 inhibition. Conclusively, we find that CRC cell lines presented with distinct responses to BH3 mimetics that can in part be predicted by their CMS profile and KRAS/BRAF mutations. Overall, almost all CRC lines share sensitivity in the nanomolar range to combined MCL-1 and BCL-XL targeting suggesting that this would be the preferred approach to target these cancers. MDPI 2021-04-07 /pmc/articles/PMC8067732/ /pubmed/33917026 http://dx.doi.org/10.3390/ijms22083811 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Zhang, Le
Ramesh, Prashanthi
Steinmetz, Maxime
Medema, Jan Paul
BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
title BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
title_full BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
title_fullStr BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
title_full_unstemmed BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
title_short BH3 Mimetic Sensitivity of Colorectal Cancer Cell Lines in Correlation with Molecular Features Identifies Predictors of Response
title_sort bh3 mimetic sensitivity of colorectal cancer cell lines in correlation with molecular features identifies predictors of response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067732/
https://www.ncbi.nlm.nih.gov/pubmed/33917026
http://dx.doi.org/10.3390/ijms22083811
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