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

doi:10.3390/cells10040716

2021

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Title:: Constitutive Cell Proliferation Regulating Inhibitor of Protein Phosphatase 2A (CIP2A) Mediates Drug Resistance to Erlotinib in an EGFR Activating Mutated NSCLC Cell Line.
Document type:: Article; Journal Article; Research Support, Non-U.S. Gov't
Author(s):: 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
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 NSCLC.
Journal title abbreviation:: Cells
Year:: 2021
Journal volume:: 10
Journal issue:: 4
Fulltext / DOI:: doi:10.3390/cells10040716
Pubmed ID:: http://view.ncbi.nlm.nih.gov/pubmed/33804833
TUM Institution:: Institut für Laboratoriumsmedizin (keine SAP-Zuordnung!)
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mediaTUM Gesamtbestand Einrichtungen Schools TUM School of Medicine and Health Departments Clinical Medicine Lehr- und Forschungskooperationen mit den Kliniken und Instituten am Deutschen Herzzentrum Institut für Laboratoriumsmedizin (DHM) (Prof. Holdenrieder)2021