p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer
Izabela Zarczynska,
Monika Gorska-Arcisz,
Alexander Jorge Cortez,
Katarzyna Aleksandra Kujawa,
Agata Małgorzata Wilk,
Andrzej Cezary Skladanowski,
Aleksandra Stanczak,
Monika Skupinska,
Maciej Wieczorek,
Katarzyna Marta Lisowska,
Rafal Sadej,
Kamila Kitowska
Affiliations
Izabela Zarczynska
Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
Monika Gorska-Arcisz
Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
Alexander Jorge Cortez
Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
Katarzyna Aleksandra Kujawa
Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
Agata Małgorzata Wilk
Department of Biostatistics and Bioinformatics, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
Andrzej Cezary Skladanowski
Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
Center for Translational Research and Molecular Biology of Cancer, Maria Sklodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeze Armii Krajowej 15, 44-102 Gliwice, Poland
Rafal Sadej
Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
Kamila Kitowska
Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland
FGFR signalling is one of the most prominent pathways involved in cell growth and development as well as cancer progression. FGFR1 amplification occurs in approximately 20% of all squamous cell lung carcinomas (SCC), a predominant subtype of non-small cell lung carcinoma (NSCLC), indicating FGFR as a potential target for the new anti-cancer treatment. However, acquired resistance to this type of therapies remains a serious clinical challenge. Here, we investigated the NSCLC cell lines response and potential mechanism of acquired resistance to novel selective FGFR inhibitor CPL304110. We found that despite significant genomic differences between CPL304110-sensitive cell lines, their resistant variants were characterised by upregulated p38 expression/phosphorylation, as well as enhanced expression of genes involved in MAPK signalling. We revealed that p38 inhibition restored sensitivity to CPL304110 in these cells. Moreover, the overexpression of this kinase in parental cells led to impaired response to FGFR inhibition, thus confirming that p38 MAPK is a driver of resistance to a novel FGFR inhibitor. Taken together, our results provide an insight into the potential direction for NSCLC targeted therapy.
