MEK inhibitors against MET-amplified non-small cell lung cancer

Abstract

Several receptor tyrosine kinases (RTKs) including EGFR, ALK, and MET have been identified as therapeutic targets in non-small cell lung cancer (NSCLC). Among the downstream pathways of RTKs, the MAPK pathway is particularly important for cancer cell proliferation, differentiation, and survival. In this study, the effects of MEK inhibitors (trametinib and PD0325901) in several NSCLC cell lines with driver gene alterations, especially RTK genes, were tested in vitro using an MTT assay, and a wide range of sensitivities was found. In particular, all the EGFR-mutated cell lines were resistant to MEK inhibitors, whereas all the MET-amplified cell lines were sensitive. A bioinformatics technique and western blot analyses showed that the PI3K/AKT pathway is more activated in EGFR-mutated NSCLC than in MET-amplified NSCLC, and a PI3K inhibitor enhanced the sensitivity to trametinib in the EGFR-mutated cell lines, suggesting that this pathway is associated with resistance to MEK inhibitors. Although the HCC827 cell line (EGFR mutation) was resistant to MEK inhibitors, the HCC827CNXR cell line, whose driver gene shifts from EGFR to MET, exhibited enhanced sensitivity to MEK inhibitors, indicating the biological importance of the MAPK pathway for MET-amplified NCSLC. Furthermore, a synergistic effect of crizotinib (a MET inhibitor) and trametinib was observed in MET-amplified NCLC cell lines. Our findings indicate that the MAPK pathway is biologically important for MET-amplified NSCLC and strongly encourage the development of combination therapy with a MET inhibitor and a MEK inhibitor against MET-amplified NSCLC.

IL‐17A promotes cell migration and invasion of glioblastoma cells via activation of PI3K/AKT signalling pathway

“…In addition, Western Blot analysis revealed that pretreatment with LY294002 abolished the IL‐17A induced up‐regulation of PI3K and AKT either total protein levels or phosphorylated protein levels respectively (* P < 0.05, ** P < 0.01) (Figure C and D). These results were similar to the results from previous studies using the same inhibitor . Taken together, the results demonstrated that the IL‐17A promoted GBM cell migration and invasion were dependent on MMP‐2/9 and Twist via activating PI3K/AKT signalling pathway.…”

Acquired BRAF Rearrangements Induce Secondary Resistance to EGFR therapy in EGFR-Mutated Lung Cancers

“…Treatment with trametinib alone decreased the growth of all cell lines with EGFR mutation alone or with a BRAF fusion; cell lines with the BRAF fusion were more sensitive, which is consistent with published data showing only limited activity of MEK inhibitors in EGFR-mutated cell lines. 20 Indeed, we found that a maximum inhibition of cell growth of only 50% was achieved by trametinib (results not shown). This may indicate that a subpopulation of cells from lines expressing a BRAF fusion can still survive after MEK inhibition.…”

Hepatocyte growth factor produced in lung fibroblasts enhances non-small cell lung cancer cell survival and tumor progression

“…However, another trial targeting Asian patients with EGFR-WT non-squamous NSCLC was prematurely terminated due to the increased incidence of interstitial lung disease in patient group treated with erlotinib and tivantinib, although preliminary data revealed that the PFS was longer in that group [ 20 ]. Met amplification is an excellent predictor of sensitivity to Met inhibitors such as PHA-665752 and crizotinib [ 22 , 23 ]. Impaired Met degradation mediated by Met exon 14 mutations has also been documented in NSCLC [ 24 – 26 ].…”