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p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer

Authors :
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
Source :
Cells, Vol 10, Iss 12, p 3363 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

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.

Details

Language :
English
ISSN :
20734409
Volume :
10
Issue :
12
Database :
Directory of Open Access Journals
Journal :
Cells
Publication Type :
Academic Journal
Accession number :
edsdoj.20c7d115e66647a98af62b0e7ef4ca88
Document Type :
article
Full Text :
https://doi.org/10.3390/cells10123363