Cargando…

Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line

Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell prolifera...

Descripción completa

Detalles Bibliográficos
Autores principales: Saafan, Hisham, Alahdab, Ahmad, Michelet, Robin, Gohlke, Linus, Ziemann, Janine, Holdenrieder, Stefan, McLaughlin, Katie-May, Wass, Mark N., Cinatl, Jindrich, Michaelis, Martin, Kloft, Charlotte, Ritter, Christoph A
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103245/
https://www.ncbi.nlm.nih.gov/pubmed/33804833
http://dx.doi.org/10.3390/cells10040716
_version_ 1783689279966281728
author Saafan, Hisham
Alahdab, Ahmad
Michelet, Robin
Gohlke, Linus
Ziemann, Janine
Holdenrieder, Stefan
McLaughlin, Katie-May
Wass, Mark N.
Cinatl, Jindrich
Michaelis, Martin
Kloft, Charlotte
Ritter, Christoph A
author_facet Saafan, Hisham
Alahdab, Ahmad
Michelet, Robin
Gohlke, Linus
Ziemann, Janine
Holdenrieder, Stefan
McLaughlin, Katie-May
Wass, Mark N.
Cinatl, Jindrich
Michaelis, Martin
Kloft, Charlotte
Ritter, Christoph A
author_sort Saafan, Hisham
collection PubMed
description Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867–0.954) vs. 0.585 (95%CI 0.568–0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1–58.8 µM) vs. 73.0 µM (95%CI 60.4–111 µM), respectively) in the concentration–effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC.
format Online
Article
Text
id pubmed-8103245
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher MDPI
record_format MEDLINE/PubMed
spelling pubmed-81032452021-05-08 Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line Saafan, Hisham Alahdab, Ahmad Michelet, Robin Gohlke, Linus Ziemann, Janine Holdenrieder, Stefan McLaughlin, Katie-May Wass, Mark N. Cinatl, Jindrich Michaelis, Martin Kloft, Charlotte Ritter, Christoph A Cells Article Exploring mechanisms of drug resistance to targeted small molecule drugs is critical for an extended clinical benefit in the treatment of non-small cell lung cancer (NSCLC) patients carrying activating epidermal growth factor receptor (EGFR) mutations. Here, we identified constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) in the HCC4006rErlo0.5 NSCLC cell line adapted to erlotinib as a model of acquired drug resistance. Constitutive CIP2A resulted in a constitutive activation of Akt signaling. The proteasome inhibitor bortezomib was able to reduce CIP2A levels, which resulted in an activation of protein phosphatase 2A and deactivation of Akt. Combination experiments with erlotinib and bortezomib revealed a lack of interaction between the two drugs. However, the effect size of bortezomib was higher in HCC4006rErlo0.5, compared to the erlotinib-sensitive HCC4006 cells, as indicated by an increase in Emax (0.911 (95%CI 0.867–0.954) vs. 0.585 (95%CI 0.568–0.622), respectively) and decrease in EC50 (52.4 µM (95%CI 46.1–58.8 µM) vs. 73.0 µM (95%CI 60.4–111 µM), respectively) in the concentration–effect model, an earlier onset of cell death induction, and a reduced colony surviving fraction (0.38 ± 0.18 vs. 0.95 ± 0.25, respectively, n = 3, p < 0.05). Therefore, modulation of CIP2A with bortezomib could be an interesting approach to overcome drug resistance to erlotinib treatment in NSCLC. MDPI 2021-03-24 /pmc/articles/PMC8103245/ /pubmed/33804833 http://dx.doi.org/10.3390/cells10040716 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 (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Saafan, Hisham
Alahdab, Ahmad
Michelet, Robin
Gohlke, Linus
Ziemann, Janine
Holdenrieder, Stefan
McLaughlin, Katie-May
Wass, Mark N.
Cinatl, Jindrich
Michaelis, Martin
Kloft, Charlotte
Ritter, Christoph A
Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line
title Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line
title_full Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line
title_fullStr Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line
title_full_unstemmed Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line
title_short Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line
title_sort constitutive cell proliferation regulating inhibitor of protein phosphatase 2a (cip2a) mediates drug resistance to erlotinib in an egfr activating mutated nsclc cell line
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103245/
https://www.ncbi.nlm.nih.gov/pubmed/33804833
http://dx.doi.org/10.3390/cells10040716
work_keys_str_mv AT saafanhisham constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT alahdabahmad constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT micheletrobin constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT gohlkelinus constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT ziemannjanine constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT holdenriederstefan constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT mclaughlinkatiemay constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT wassmarkn constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT cinatljindrich constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT michaelismartin constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT kloftcharlotte constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline
AT ritterchristopha constitutivecellproliferationregulatinginhibitorofproteinphosphatase2acip2amediatesdrugresistancetoerlotinibinanegfractivatingmutatednsclccellline