Alectinib and lorlatinib function by modulating EMT-related proteins and MMPs in NSCLC metastasis

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.

Heterogeneity and plasticity of epithelial–mesenchymal transition (EMT) in cancer metastasis: Focusing on partial EMT and regulatory mechanisms

“…For example, lapatinib, an orally active drug for solid tumours through targeting HER2 and EGFR pathways, has been reported to inhibit the cellular EMT program in multiple cancers 107–109 . Consistently, Clinical drugs targeting ALK, such as alectinib and lorlatinib, have been found to inhibit cellular EMT signalling in lung cancer 110 . Gamma secretase inhibitors of Notch signalling has been confirmed to inhibit EMT in ovarian cancer 111 .…”

“… 107 , 108 , 109 Consistently, Clinical drugs targeting ALK, such as alectinib and lorlatinib, have been found to inhibit cellular EMT signalling in lung cancer. 110 Gamma secretase inhibitors of Notch signalling has been confirmed to inhibit EMT in ovarian cancer. 111 Therefore, it has become an increasingly promising anti‐tumour strategy by blocking EMT signalling pathway in cancer cells.…”

Cerebrospinal fluid exosomal protein alterations via proteomic analysis of NSCLC with leptomeningeal carcinomatosis

“…FN1 is also known to play regulatory roles in NSCLC brain metastasis [ 31 ]. When epithelial cells obtain the mesenchymal phenotype, disruption of intercellular tight junctions and blood-brain barrier will facilitate cell migration [ 32 ]. FN1 was detected among LC and NSCLC group by combination of label free and PRM based proteomics and bioinformatics analysis.…”

Micro-ribonucleic acids (miRNAs) and a proteomic profile in lung adenocarcinoma cases with brain metastasis

“…Serpin Family A Member 1 was significantly differentially expressed between the BM and LP groups in the current study and another report ( 17 ). It has been reported that epithelial-to-mesenchymal transition–associated proteins and matrix metalloproteinases contribute to BM by modulating the blood-brain barrier ( 18 ). In addition, the high expression of inner membrane mitochondrial protein is closely associated with advanced disease stage and poor patient prognosis in LAC ( 19 ).…”