KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)

Abstract Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyros...

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Autores principales:	Felix Glaser, Petra Hundehege, Etmar Bulk, Luca Matteo Todesca, Sandra Schimmelpfennig, Elke Nass, Thomas Budde, Sven G. Meuth, Albrecht Schwab
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/ea44233d01d54406b574d27a85bdab53
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spelling	oai:doaj.org-article:ea44233d01d54406b574d27a85bdab532021-12-02T18:02:15ZKCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)10.1038/s41598-021-97406-02045-2322https://doaj.org/article/ea44233d01d54406b574d27a85bdab532021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97406-0https://doaj.org/toc/2045-2322Abstract Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs. On the other hand, KCa3.1 channels contribute to NSCLC progression so that elevated KCa3.1 expression is a strong predictor of poor NSCLC patient prognosis. The present study tests whether blocking KCa3.1 channels increases the sensitivity of NSCLC cells towards the EGFR TKI erlotinib and overcomes drug resistance. mRNA expression of KCa3.1 channels in erlotinib-sensitive and -resistant NSCLC cells was analysed in datasets from Gene expression omnibus (GEO) and ArrayExpress. We assessed proliferation and migration of NSCLC cells. These (live cell-imaging) experiments were complemented by patch clamp experiments and Western blot analyses. We identified three out of four datasets comparing erlotinib-sensitive and -resistant NSCLC cells which revealed an altered expression of KCa3.1 mRNA in erlotinib-resistant NSCLC cells. Therefore, we evaluated the combined effect of erlotinib and the KCa3.1 channel inhibition with sencapoc. Erlotinib elicits a dose-dependent inhibition of migration and proliferation of NSCLC cells. The simultaneous application of the KCa3.1 channel blocker senicapoc increases the sensitivity towards a low dose of erlotinib (300 nmol/L) which by itself has no effect on migration and proliferation. Partial erlotinib resistance can be overcome by KCa3.1 channel blockade. The sensitivity towards erlotinib as well as the potentiating effect of KCa3.1 blockade is further increased by mimicking hypoxia. Our results suggest that KCa3.1 channel blockade may constitute a therapeutic concept for treating NSCLC and overcome EGFR TKI resistance. We propose that this is due to complementary mechanisms of action of both blockers.Felix GlaserPetra HundehegeEtmar BulkLuca Matteo TodescaSandra SchimmelpfennigElke NassThomas BuddeSven G. MeuthAlbrecht SchwabNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Felix Glaser Petra Hundehege Etmar Bulk Luca Matteo Todesca Sandra Schimmelpfennig Elke Nass Thomas Budde Sven G. Meuth Albrecht Schwab KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
description	Abstract Non-small cell lung cancer (NSCLC) has a poor prognosis with a 5 year survival rate of only ~ 10%. Important driver mutations underlying NSCLC affect the epidermal growth factor receptor (EGFR) causing the constitutive activation of its tyrosine kinase domain. There are efficient EGFR tyrosine kinase inhibitors (TKIs), but patients develop inevitably a resistance against these drugs. On the other hand, KCa3.1 channels contribute to NSCLC progression so that elevated KCa3.1 expression is a strong predictor of poor NSCLC patient prognosis. The present study tests whether blocking KCa3.1 channels increases the sensitivity of NSCLC cells towards the EGFR TKI erlotinib and overcomes drug resistance. mRNA expression of KCa3.1 channels in erlotinib-sensitive and -resistant NSCLC cells was analysed in datasets from Gene expression omnibus (GEO) and ArrayExpress. We assessed proliferation and migration of NSCLC cells. These (live cell-imaging) experiments were complemented by patch clamp experiments and Western blot analyses. We identified three out of four datasets comparing erlotinib-sensitive and -resistant NSCLC cells which revealed an altered expression of KCa3.1 mRNA in erlotinib-resistant NSCLC cells. Therefore, we evaluated the combined effect of erlotinib and the KCa3.1 channel inhibition with sencapoc. Erlotinib elicits a dose-dependent inhibition of migration and proliferation of NSCLC cells. The simultaneous application of the KCa3.1 channel blocker senicapoc increases the sensitivity towards a low dose of erlotinib (300 nmol/L) which by itself has no effect on migration and proliferation. Partial erlotinib resistance can be overcome by KCa3.1 channel blockade. The sensitivity towards erlotinib as well as the potentiating effect of KCa3.1 blockade is further increased by mimicking hypoxia. Our results suggest that KCa3.1 channel blockade may constitute a therapeutic concept for treating NSCLC and overcome EGFR TKI resistance. We propose that this is due to complementary mechanisms of action of both blockers.
format	article
author	Felix Glaser Petra Hundehege Etmar Bulk Luca Matteo Todesca Sandra Schimmelpfennig Elke Nass Thomas Budde Sven G. Meuth Albrecht Schwab
author_facet	Felix Glaser Petra Hundehege Etmar Bulk Luca Matteo Todesca Sandra Schimmelpfennig Elke Nass Thomas Budde Sven G. Meuth Albrecht Schwab
author_sort	Felix Glaser
title	KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
title_short	KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
title_full	KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
title_fullStr	KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
title_full_unstemmed	KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)
title_sort	kca channel blockers increase effectiveness of the egf receptor tk inhibitor erlotinib in non-small cell lung cancer cells (a549)
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/ea44233d01d54406b574d27a85bdab53
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KCa channel blockers increase effectiveness of the EGF receptor TK inhibitor erlotinib in non-small cell lung cancer cells (A549)

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