Abstract
Drug resistance can notably restrict clinical applications of gefitinib that is a commonly used EGFR-tyrosine kinase inhibitors (EGFR-TKIs) for non-small cell lung cancer (NSCLC). The attempts in exploring novel drug targets and reversal strategies are still needed, since gefitinib resistance has not been fully addressed. Protease-activated receptor 2 (PAR2), a G protein-coupled receptor, possesses a transactivation with EGFR to initiate a variety of intracellular signal transductions, but there is a lack of investigations on the role of PAR2 in gefitinib resistance. This study established that protease-activated receptor 2 (PAR2), actively participated in NSCLC resistant to gefitinib. PAR2 expression was significantly up-regulated when NSCLC cells or tumor tissues became gefitinib resistance. PAR2 inhibition notably enhanced gefitinib to modulate EGFR transactivation, cell viability, migration and apoptosis in gefitinib-sensitive and-resistant NSCLC cells, suggesting its reversal effects in gefitinib resistance. Meanwhile, the combination of a PAR2 inhibitor (P2pal-18S) and gefitinib largely blocked ERK phosphorylation and epithelial-mesenchymal transition (EMT) compared to gefitinib alone. Importantly, we probed its underlying mechanism and uncovered that PAR2 blockade sensitized gefitinib and reversed its resistance mainly via β-arrestin-EGFR-ERK signaling axis. These effects of PAR2 inhibition were further confirmed by the in vivo study which showed that P2pal-18S reactivated gefitinib to inhibit tumor growth via restricting ERK activation. Taken together, this study could not only reveal a new mechanism of receptor-mediated transactivation to modulate drug resistance, but also provide a novel drug target and direction for overcoming gefitinib resistance in NSCLC.
Highlights
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers which is the leading cause of cancer-related death worldwide (Gridelli et al, 2015; Herbst et al, 2018)
For deeply understanding of its molecular mechanism, we looked into the role of the receptor transactivation-mediated signaling pathway in non-small cell lung cancer (NSCLC) cell functions related to gefitinib resistance. β-arrestin is considered as a crucial factor regulating epidermal growth factor receptor (EGFR) transactivation while Protease-activated receptor 2 (PAR2) could promote β-arrestin to drive EGFR transactivation and downstream ERK signaling (Köse, 2017)
We found that PAR2 expression was notably elevated in NSCLC cells during the generation of gefitinib resistance (Figure 1G) and this was consistent with a previous multiple analysis of GPCRs expressions in gefitinib-resistant NSCLC cells (Kuzumaki et al, 2012)
Summary
Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancers which is the leading cause of cancer-related death worldwide (Gridelli et al, 2015; Herbst et al, 2018). Gefitinib as the first-generation EGFR-TKI has markedly prolonged the overall survival of NSCLC patients; PAR2 in Lung Cancer Resistance drug resistance has been eventually harboured leading to the ultimate failure of clinical treatments (Hirsch et al, 2016). The third-generation EGFR-TKI, osimertinib, has been successfully developed to overcome EGFR-T790M mutated resistance to gefitinib (Jänne et al, 2015), other resistance mechanisms have not been clinically well-addressed due to its diverse and complicated characteristics. It is an urgent need for exploring novel drug strategies targeting NSCLC resistant to gefitinib depending on other receptors, signaling pathways or histological changes
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