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.
Highlights
Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers[1]
While these findings clearly point to a role of K Ca3.1 channels in NSCLC progression, they do not address the clinical problem of resistance against tyrosine kinase inhibitors (TKI)
We identified three ion channel genes that are expressed at a reduced level in erlotinib-resistant NSCLC cell lines
Summary
Non-small cell lung cancer (NSCLC) accounts for the majority of all lung cancers[1]. Even after complete resection of early stage NSCLC ~ 50% of the patients will die from recurring tumors, and the mean 5 year survival rate of European lung cancer patients is only 13%2 It has become clear, that an efficient therapy needs to take into account the pathological classification[1] and the presence of genetic alterations[3, 4]. K Ca3.1 channels regulate the expression of the intercellular adhesion molecule (ICAM)[1] and adhesion of NSCLC cells to endothelial cells which is an important step of the metastatic cascade[10] While these findings clearly point to a role of K Ca3.1 channels in NSCLC progression, they do not address the clinical problem of resistance against tyrosine kinase inhibitors (TKI).
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