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p38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer
Izabela Zarczynska1, Monika Gorska-Arcisz1, Alexander Jorge Cortez2
1Department of Molecular Enzymology and Oncology, Intercollegiate Faculty of Biotechnology, University of Gdansk and Medical University of Gdansk, Debinki 1, 80-211 Gdansk, Poland.
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.
Insights
Fibroblast growth factor receptor (FGFR) inhibitors show promise for non-small cell lung cancer (NSCLC). This study reveals p38 MAPK signaling as a key mechanism of acquired resistance to FGFR inhibitors like CPL304110.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Fibroblast growth factor receptor (FGFR) signaling is crucial for cell growth, development, and cancer progression.
- FGFR1 amplification is observed in approximately 20% of squamous cell lung carcinomas (SCC), a subtype of non-small cell lung carcinoma (NSCLC), highlighting FGFR as a therapeutic target.
- Acquired resistance to FGFR-targeted therapies presents a significant clinical challenge in NSCLC treatment.
Purpose of the Study:
- To investigate the response of NSCLC cell lines to the novel selective FGFR inhibitor CPL304110.
- To elucidate the potential mechanisms of acquired resistance to CPL304110 in NSCLC.
- To identify therapeutic strategies to overcome resistance to FGFR inhibition in NSCLC.
Main Methods:
- Utilized NSCLC cell lines and their resistant variants to study drug response.
- Analyzed gene and protein expression, including p38 and MAPK signaling pathways.
- Investigated the effect of p38 inhibition and overexpression on sensitivity to CPL304110.
Main Results:
- Resistant NSCLC variants exhibited upregulated p38 expression/phosphorylation and enhanced MAPK signaling compared to sensitive counterparts.
- Inhibition of p38 signaling restored sensitivity to CPL304110 in resistant NSCLC cells.
- Overexpression of p38 kinase in parental NSCLC cells led to reduced sensitivity to FGFR inhibition, confirming p38 MAPK as a resistance driver.
Conclusions:
- p38 MAPK signaling is a critical mechanism driving acquired resistance to the novel FGFR inhibitor CPL304110 in NSCLC.
- Targeting p38 MAPK in combination with FGFR inhibitors may represent a viable therapeutic strategy for overcoming resistance in NSCLC.
- These findings offer insights into potential directions for targeted NSCLC therapy by addressing resistance mechanisms.
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