P38 Mediates Resistance to FGFR Inhibition in Non-Small Cell Lung Cancer.

Izabela Zarczynska,Maciej Wieczorek,Agata Małgorzata Wilk,Kamila Kitowska,Monika Gorska-Arcisz,Alexander Jorge Cortez,Monika Skupinska,Aleksandra Stanczak,Katarzyna Marta Lisowska,Andrzej Cezary Skladanowski,Rafal Sadej,Katarzyna Aleksandra Kujawa

doi:10.3390/cells10123363

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.

Highlights

We analysed the response of five lung cancer cell lines to the new FGFR inhibitor, CPL304110
Evaluation of cell proliferation revealed that NCI-H1581 and NCIH1703 cells strongly responded to CPL304110, showing a significant growth reduction with IC50 < 1 μM, while DMS114, NCI-H2170, and NCI-H520 cells were less sensitive to FGFR inhibition (IC50 ≥ 1 μM) (Figure 1A)
Further investigation revealed that response to CPL304110 correlated with FGFR protein expression, as Western blotting analysis showed the highest FGFR1-4 expression levels in NCI-H1581 and NCI-H1703 among analysed cell lines (Figure 1C)

Summary

Introduction

Gene alterations and rearrangements in EGFR, ALK, ROS1, BRAF, or NTRK typical for ADC were discovered in the last two decades, which led to the development of targeted therapies using tyrosine kinase inhibitors (TKI) [2]. Such drugs, applied as an alternative to conventional chemotherapy and radiotherapy in first-line treatment of advanced ADC, have significantly improved clinical outcomes. Several clinical trials are underway, developing the targeted therapies for lung squamous cell carcinomas (SCC)

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Results

Conclusion