E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells

Abstract

Malignant mesothelioma (MM) is an aggressive tumor commonly caused by asbestos exposure after a long latency. Focal adhesion kinase (FAK) inhibitors inhibit the cell growth of Merlin-deficient MM cells; however, their clinical efficacy has not been clearly determined. The aim of this study was to evaluate the growth inhibitory effect of the FAK inhibitor VS-4718 on MM cell lines and identify biomarkers for its efficacy. Although most Merlin-deficient cell lines were sensitive to VS-4718 compared with control MeT-5A cells, a subset of these cell lines exhibited resistance to this drug. Microarray and qRT-PCR analyses using RNA isolated from Merlin-deficient MM cell lines revealed a significant correlation between E-cadherin mRNA levels and VS-4718 resistance. Merlin- and E-cadherin-negative Y-MESO-22 cells underwent apoptosis upon treatment with a low concentration of VS-4718, whereas Merlin-negative, E-cadherin-positive Y-MESO-9 cells did not undergo VS-4718-induced apoptosis. Furthermore, E-cadherin knockdown in Merlin-negative MM cells significantly sensitized cells to VS-4718 and induced apoptotic cell death upon VS-4718 treatment. Together, our results suggest that E-cadherin serves as a predictive biomarker for molecular target therapy with FAK inhibitors for patients with mesothelioma and that its expression endows MM cells with resistance to FAK inhibitors.

Assessment of signaling pathway inhibitors and identification of predictive biomarkers in malignant pleural mesothelioma

“…Defactinib sensitivity is also not related to E-cadherin (CDH1 gene) gene and protein expression in NF2mutated MPM as suggested by Kato et al (Fig. S7c-d) [32]. However, our results demonstrated that defactinib sensitivity is strongly correlated to FAK activity especially in epithelioid MPM.…”

“…We did not find a significant correlation between the protein expression or the mutational status of NF2 gene and defactinib sensitivity. A lack of significant association between merlin expression and VS-4718 sensitivity was also reported in a recent study by Kato et al, contrary to what was previously suggested by Shapiro et al [16], [32]. Defactinib sensitivity is also not related to E-cadherin (CDH1 gene) gene and protein expression in NF2mutated MPM as suggested by Kato et al (Fig.…”

DNA methylation profiling of asbestos-treated MeT5A cell line reveals novel pathways implicated in asbestos response

“…By analysing differentially methylated signals modulated in a dose-dependent manner by crocidolite exposure, we identified genes coding molecules involved in cell adhesion, such as Neurexin 2 (NRXN2), Laminin Subunit Gamma 1 (LAMC1) and Beta 4 (LAMB4) genes. The expression changes in cell adhesion-related molecules are known to be accompanied with EMT in MPM and the process of cell adhesion has been shown to be important both in the initial spreading and in the progression of the tumour (Kato et al 2017).…”

Targeting the complexity of Src signalling in the tumour microenvironment of pancreatic cancer: from mechanism to therapy

“…In addition, FAK inhibitors such as PF-00562271 are well tolerated and hence show significant promise for the treatment of PDAC [131,196]. Promising preclinical data in malignant pleural mesothelioma, ovarian and other solid tumours suggest that therapeutic responsiveness to FAK inhibition may be guided by Merlin loss [197,198] or E-cadherin levels [199]. This is supported by positive data from two phase I studies (NCT01138033, NCT01938443) in advanced solid tumours, where improved response to the FAK inhibitor GSK2256098 was observed in Merlin-negative mesothelioma [131,133].…”