Abstract
Most advanced non-small cell lung cancer (NSCLC) patients are accompanied by brain metastasis which is the major cause of increased mortality. The fusion rearrangement of anaplastic lymphoma kinase (ALK) gene is an important feature of brain metastasis in lung cancer. The novel ALK inhibitors alectinib and lorlatinib are shown to be effective against NSCLC brain metastasis, while their underlying mechanism of action is unclear. Epithelial–mesenchymal transition (EMT) proteins and matrix metalloproteinases (MMPs) play important roles in brain metastasis by regulating the blood-brain barrier (BBB). To reveal the molecular function of alectinib and lorlatinib, we explored their effects on the cellular levels of EMT markers: VIM and FN1 and the matrix metalloproteinases MMP-9 and MMP-7. The mRNA and protein levels of VIM, FN1, MMP-9, and MMP-7 were elevated in H3122 cells. However, upon alectinib and lorlatinib treatment, the levels were significantly reduced. Similar results were obtained when these experiments were performed either in a dose-dependent or time-dependent manner. Furthermore, alectinib and lorlatinib also inhibited the cell viability and migration of H3122 cells. Interestingly, in comparison to individual drugs, the combination of alectinib and lorlatinib was found to be substantially more effective. Overall, these results suggest that alectinib and lorlatinib possibly function through the downregulation of MMPs and EMT in NSCLC metastasis.
Highlights
Lung cancer is a grave public health concern worldwide [1]
The results showed that the mRNA expressions of VIM, fibronectin 1 (FN1), matrix metalloproteinases (MMPs)-9, and MMP-7 were increased in H3112 cells
When western blot analysis was carried out to measure the protein levels, results showed that the protein levels of VIM, FN1, MMP-9, and MMP-7 were reduced by 0.1 μM alectinib and 0.1 μM lorlatinib in H3112 cells (Figure 1B and C; ***p < 0.05, ###p < 0.01, vs. 16HBE)
Summary
Lung cancer is a grave public health concern worldwide [1]. It is ranked first in men and among the top three in women based on high incidence and mortality rate. The rates are even further rising [2]. 3-7% of NSCLC is due to the rearrangement of the carcinogenic anaplastic lymphoma kinase (ALK) gene. Most of these patients later submit to brain metastasis which is the leading cause for higher mortality [4]. The prognosis of brain metastasis is poor and the median survival time of untreated brain metastases may be only 7 months, even though the median survival time of untreated brain metastases is generally
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
