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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, and others. (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 (4). p. 716. ISSN 2073-4409. (doi:10.3390/cells10040716) (KAR id:87534)

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Official URL
https://doi.org/10.3390/cells10040716

Abstract

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 NSCL

Item Type: Article
DOI/Identification number: 10.3390/cells10040716
Uncontrolled keywords: non-small cell lung cancer; epidermal growth factor receptor; drug resistance; cell proliferation regulating inhibitor of protein phosphatase 2A; bortezomib
Subjects: R Medicine > RC Internal medicine > RC254 Neoplasms. Tumors. Oncology
R Medicine > RM Therapeutics. Pharmacology
Divisions: Divisions > Division of Natural Sciences > School of Biosciences
Depositing User: Martin Michaelis
Date Deposited: 10 Apr 2021 08:11 UTC
Last Modified: 12 Apr 2021 08:48 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/87534 (The current URI for this page, for reference purposes)
Wass, Mark N.: https://orcid.org/0000-0001-5428-6479
Michaelis, Martin: https://orcid.org/0000-0002-5710-5888
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