Next Article in Journal
Assessment of the Neuroprotective and Stemness Properties of Human Wharton’s Jelly-Derived Mesenchymal Stem Cells under Variable (5% vs. 21%) Aerobic Conditions
Next Article in Special Issue
Distinct Classes of Flavonoids and Epigallocatechin Gallate, Polyphenol Affects an Oncogenic Mutant p53 Protein, Cell Growth and Invasion in a TNBC Breast Cancer Cell Line
Previous Article in Journal
Deletion of the Actin-Associated Tropomyosin Tpm3 Leads to Reduced Cell Complexity in Cultured Hippocampal Neurons—New Insights into the Role of the C-Terminal Region of Tpm3.1
Previous Article in Special Issue
Pre-Clinical Evaluation of the Proteasome Inhibitor Ixazomib against Bortezomib-Resistant Leukemia Cells and Primary Acute Leukemia Cells
Article

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

1
Institute of Pharmacy, Clinical Pharmacy, University of Greifswald, Friedrich-Ludwig-Jahn-Str. 17, 17489 Greifswald, Germany
2
Department of Clinical Pharmacy and Biochemistry, Institute of Pharmacy, Freie Universitaet Berlin, 14195 Berlin, Germany
3
Central Unit for Infection Prevention and Control, University Medicine Greifswald, 17475 Greifswald, Germany
4
Institute of Laboratory Medicine, German Heart Center, Munich Technical University, 80636 Munich, Germany
5
Industrial Biotechnology Centre, School of Biosciences, University of Kent, Canterbury CT2 7NJ, UK
6
Institute of Medical Virology, Goethe-University, 60596 Frankfurt am Main, Germany
*
Author to whom correspondence should be addressed.
Academic Editor: Steven G. Gray
Cells 2021, 10(4), 716; https://doi.org/10.3390/cells10040716
Received: 31 December 2020 / Revised: 15 March 2021 / Accepted: 17 March 2021 / Published: 24 March 2021
(This article belongs to the Special Issue Studying Drug Resistance Using Cancer Cell Lines)
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. View Full-Text
Keywords: non-small cell lung cancer; epidermal growth factor receptor; drug resistance; cell proliferation regulating inhibitor of protein phosphatase 2A; bortezomib non-small cell lung cancer; epidermal growth factor receptor; drug resistance; cell proliferation regulating inhibitor of protein phosphatase 2A; bortezomib
Show Figures

Figure 1

MDPI and ACS Style

Saafan, H.; Alahdab, A.; Michelet, R.; Gohlke, L.; Ziemann, J.; Holdenrieder, S.; McLaughlin, K.-M.; Wass, M.N.; Cinatl, J., Jr.; Michaelis, M.; Kloft, C.; Ritter, C.A. Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line. Cells 2021, 10, 716. https://doi.org/10.3390/cells10040716

AMA Style

Saafan H, Alahdab A, Michelet R, Gohlke L, Ziemann J, Holdenrieder S, McLaughlin K-M, Wass MN, Cinatl J Jr., Michaelis M, Kloft C, Ritter CA. Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line. Cells. 2021; 10(4):716. https://doi.org/10.3390/cells10040716

Chicago/Turabian Style

Saafan, Hisham, Ahmad Alahdab, Robin Michelet, Linus Gohlke, Janine Ziemann, Stefan Holdenrieder, Katie-May McLaughlin, Mark N. Wass, Jindrich Cinatl Jr., Martin Michaelis, Charlotte Kloft, and Christoph A. Ritter 2021. "Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line" Cells 10, no. 4: 716. https://doi.org/10.3390/cells10040716

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Back to TopTop