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Bracht et al. J Cancer Metastasis Treat 2019;5:22 Journal of Cancer
DOI: 10.20517/2394-4722.2018.111 Metastasis and Treatment

Original Article Open Access

PIM-1 inhibition with AZD1208 to prevent osimertinib-
induced resistance in EGFR-mutation positive non-

small cell lung cancer

Jillian Wilhelmina Paulina Bracht , Niki Karachaliou , Jordi Berenguer , Manuel Fernandez-Bruno ,
1,2
2
1
1
Martyna Filipska , Carlos Pedraz-Valdunciel , Carles Codony-Servat , Jordi Codony-Servat , Rafael
1
3
1
3
Rosell 1,3,4,5
1 Pangaea Oncology, Laboratory of Molecular Biology, Quirón-Dexeus University Institute, Barcelona 08028, Spain.
2 Instituto Oncológico Dr Rosell (IOR), University Hospital Sagrat Cor, QuironSalud Group, Barcelona 08029, Spain.
3 Institut d’Investigació en Ciències Germans Trias i Pujol, Badalona 08916, Spain.
4 Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona 08916, Spain.
5 Instituto Oncológico Dr Rosell (IOR), Quirón-Dexeus University Institute, Barcelona 08028, Spain.
Correspondence to: Prof. Rafael Rosell, Institut Català d’Oncologia, Hospital Germans Trias i Pujol, Badalona 08916, Spain.
E-mail: rrosell@iconcologia.net
How to cite this article: Bracht JWP, Karachaliou N, Berenguer J, Fernandez-Bruno M, Filipska M, Pedraz-Valdunciel C, Codony-
Servat C, Codony-Servat J, Rosell R. PIM-1 inhibition with AZD1208 to prevent osimertinib-induced resistance in EGFR-mutation
positive non-small cell lung cancer. J Cancer Metastasis Treat 2019;5:22. http://dx.doi.org/10.20517/2394-4722.2018.111

Received: 30 Dec 2018 Accepted: 27 Feb 2019 Published: 26 Mar 2019

Science Editor: Yaguang Xi Copy Editor: Cai-Hong Wang Production Editor: Huan-Liang Wu

Abstract
Aim: The progression free survival of non-small cell lung cancer (NSCLC) patients has been doubled over the last
years, but still single epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) lead to incomplete
responses. Compensatory signaling pathways are activated upon single EGFR TKIs. We have shown that compounds,
which inhibit these pathways, are synergistic with EGFR TKIs. Proviral integration site for Moloney murine leukemia
virus (PIM) has been connected to cancer therapy resistance, being involved in receptor tyrosine kinase, signal
transducer and activator of transcription 3 (STAT3) and interleukin-6 signaling. We hypothesized that combined PIM
and EGFR inhibition may improve the upfront therapy of EGFR-mutation positive NSCLC.

Methods: We reviewed the literature on PIM kinases, and performed cell viability assays, gene expression analyses,
and immunoblotting experiments to reveal the mechanisms of action of the PIM inhibitor (AZD1208) alone and
combined with osimertinib in five EGFR-mutation positive NSCLC cell lines.

Results: Osimertinib alone induced the activation of signal transducer and activator of transcription 3 (STAT3)
as well as other signaling nodes. Combined osimertinib and AZD1208 yielded moderate synergistic effects in all

© The Author(s) 2019. Open Access This article is licensed under a Creative Commons Attribution 4.0
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