Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis
Open Access
- 20 October 2020
- journal article
- research article
- Published by Association of Basic Medical Sciences of FBIH in Bosnian Journal of Basic Medical Sciences
- Vol. 21 (3), 331-338
- https://doi.org/10.17305/bjbms.2020.5066
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 via the downregulation of MMPs and EMT in NSCLC metastasis.Keywords
This publication has 23 references indexed in Scilit:
- Lung cancer-associated brain metastasis: Molecular mechanisms and therapeutic optionsCellular Oncology, 2017
- Complete remission of intrathecal metastases with lorlatinib therapy in a heavily pretreated ALK-positive lung cancer patientAnti-Cancer Drugs, 2017
- EMT, cell plasticity and metastasisCancer and Metastasis Reviews, 2016
- Epidemiology of Lung CancerSurgical Oncology Clinics of North America, 2016
- Silence of fibronectin 1 increases cisplatin sensitivity of non-small cell lung cancer cell lineBiochemical and Biophysical Research Communications, 2016
- Progression and metastasis of lung cancerCancer and Metastasis Reviews, 2016
- Lung Cancer StatisticsPublished by Springer Science and Business Media LLC ,2015
- BCYRN1, a c-MYC-activated long non-coding RNA, regulates cell metastasis of non-small-cell lung cancerCancer Cell International, 2015
- Alectinib Induces a Durable (>15 Months) Complete Response in an ALK-Positive Non-Small Cell Lung Cancer Patient Who Progressed on Crizotinib With Diffuse Leptomeningeal CarcinomatosisThe Oncologist, 2015