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 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.
Author:Hisham Saafan, Ahmad Alahdab, Robin MicheletORCiD, Linus Gohlke, Janine Ziemann, Stefan Holdenrieder, Katie-May McLaughlin, Mark N. WassORCiD, Jindrich CinatlORCiDGND, Martin MichaelisORCiDGND, Charlotte Kloft, Christoph A . Ritter
Parent Title (English):Cells
Place of publication:Basel
Document Type:Article
Date of Publication (online):2021/03/24
Date of first Publication:2021/03/24
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2021/10/20
Tag:bortezomib; cell proliferation regulating inhibitor of protein phosphatase 2A; drug resistance; epidermal growth factor receptor; non-small cell lung cancer
Issue:4, art. 716
Page Number:15
First Page:1
Last Page:15
A.A. received a PhD stipend from the German Academic Exchange Service (Deutscher Akademischer Austauschdienst DAAD). We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 393148499) and the Open Access Publication Fund of the University of Greifswald.
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0