TY  - JOUR
A1  - Saafan, Hisham
A1  - Alahdab, Ahmad
A1  - Michelet, Robin
A1  - Gohlke, Linus
A1  - Ziemann, Janine
A1  - Holdenrieder, Stefan
A1  - McLaughlin, Katie-May
A1  - Wass, Mark N.
A1  - Cinatl, Jindrich
A1  - Michaelis, Martin
A1  - Kloft, Charlotte
A1  - Ritter, Christoph A .
T1  - Constitutive cell proliferation regulating inhibitor of protein phosphatase 2A (CIP2A) mediates drug resistance to erlotinib in an EGFR activating mutated NSCLC cell line
T2  - Cells
N2  - 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.
KW  - non-small cell lung cancer
KW  - epidermal growth factor receptor
KW  - drug resistance
KW  - cell proliferation regulating inhibitor of protein phosphatase 2A
KW  - bortezomib
Y1  - 2021
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/62139
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-621391
SN  - 2073-4409
N1  - 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.
VL  - 10
IS  - 4, art. 716
SP  - 1
EP  - 15
PB  - MDPI
CY  - Basel
ER  -