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

Our plain-English summary of E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells, by T. Kato, T. Sato, K. Yokoi, et al (Oncogene, 2017).

The study

• Authors: T. Kato, T. Sato, K. Yokoi, Y. Sekido
• Journal: Oncogene
• Published: 2017;36(39):5522-5531
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

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.

In plain English

This was mainly a laboratory study of cultured cancer cells. It did not study asbestos exposure or test the drug in patients. The authors tested the drug VS-4718, a focal adhesion kinase (FAK) inhibitor, on 21 malignant mesothelioma cell lines and on MeT-5A, an immortalized human mesothelial line used for comparison. Only 8 of the 21 lines made the protein Merlin. In 11 of 21 lines, VS-4718 reached half-maximal growth inhibition (IC50) below 2.2 μM, the IC50 for MeT-5A. The drug's effect did not differ significantly between Merlin-positive and Merlin-negative lines (P = 0.17). Among the 13 Merlin-negative lines, higher E-cadherin mRNA went with greater drug resistance (r = 0.872). Of two Merlin-negative lines, the E-cadherin-negative one underwent apoptosis (cell death) with the drug and the E-cadherin-positive one did not. Reducing E-cadherin made Merlin-negative cells more sensitive. In Cancer Genome Atlas data on 56 patients, low levels of both E-cadherin and NF2 mRNA were associated with the poorest survival. The authors concluded that E-cadherin may serve as a biomarker for FAK inhibitor treatment, and said this needs testing in future clinical studies.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory (in vitro) study of human malignant mesothelioma cell lines grown in a three-dimensional Matrigel culture. It also reanalyzed the authors' earlier microarray data and public Cancer Genome Atlas patient survival data.
• Who was studied: 21 malignant mesothelioma cell lines, plus the immortalized human mesothelial cell line MeT-5A as a control. Fifteen lines were Japanese lines established in the authors' laboratory, four were purchased from the American Type Culture Collection, and two were gifts. The survival analysis used Cancer Genome Atlas data on 56 patients with mesothelioma.
• Exposure: No asbestos or fiber exposure was studied. The exposure tested was the FAK inhibitor drug VS-4718, applied to cells at various concentrations. The authors also experimentally changed Merlin and E-cadherin levels in the cells.
• Main results:
  • Merlin protein was detected in 8 of the 21 mesothelioma cell lines.
  • VS-4718 inhibited growth of 11 of 21 mesothelioma cell lines with IC50 values (concentration giving half-maximal growth inhibition) below 2.2 μM. 2.2 μM was the IC50 value for the control MeT-5A line.
  • The effect of VS-4718 did not differ significantly between Merlin-positive and Merlin-negative cell lines (P = 0.17). Five Merlin-negative lines were less sensitive than MeT-5A.
  • Adding full-length Merlin to Merlin-negative Y-MESO-22 cells increased resistance to VS-4718. The IC50 was 0.48 μM, compared with 0.17 μM in control cells. This was still lower than the 2.2 μM IC50 of MeT-5A.
  • In the 13 Merlin-negative cell lines, E-cadherin mRNA levels were significantly correlated with resistance to VS-4718 (r = 0.872, P less than 0.001). No such correlation was seen in Merlin-positive lines, or for other markers (N-cadherin, Snail, Slug, Twist).
  • At the protein level, E-cadherin-positive mesothelioma cell lines were significantly more resistant to VS-4718 than E-cadherin-negative lines (P = 0.03).
  • Both Y-MESO-22 and Y-MESO-9 cells lacked Merlin. After VS-4718 treatment, the E-cadherin-negative Y-MESO-22 cells showed a marker of apoptosis (cleaved caspase-3), and the E-cadherin-positive Y-MESO-9 cells did not.
  • Reducing (knocking down) E-cadherin in Merlin-negative, E-cadherin-positive Y-MESO-25 cells increased growth inhibition by VS-4718 compared with control cells. A similar effect was seen in Y-MESO-45 cells.
  • In Cancer Genome Atlas data on 56 patients with mesothelioma, low expression of both E-cadherin and NF2 mRNA was significantly correlated with the poorest overall survival (P = 0.0072, high/high group compared with low/low group).
• The authors' conclusion: The authors concluded that E-cadherin confers resistance to the FAK inhibitor in mesothelioma cells. They said it may serve as a biomarker for judging how well FAK inhibitors work in patients with mesothelioma.
• Limitations the authors state:
  • The biological basis for the link between E-cadherin and VS-4718 resistance is not yet explained.
  • The proposed biomarkers have not been tested in patients and need evaluation in future clinical studies.
  • The mechanisms of sensitivity and resistance to VS-4718 remain unknown.
  • The comparison of E-cadherin levels across tumor subtypes in patient data may have been limited by small numbers of biphasic and sarcomatoid cases.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Merlin, Malignant Mesothelioma, Asbestos Exposure, Latency, Biomarker, MeT-5A Cells, Apoptosis, Mesothelioma.

Related studies

• The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM) — M.L. Yuen, L. Zhuang, et al. (2021)
• Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship — I.M. Shapiro, V.N. Kolev, et al. (2014)
• Analyses of merlin/NF2 connection to FAK inhibitor responsiveness in serous ovarian cancer — N.R. Shah, I. Tancioni, et al. (2014)
• A phase I, pharmacokinetic and pharmacodynamic study of GSK2256098, a focal adhesion kinase inhibitor, in patients with advanced solid tumors — J.C. Soria, H.K. Gan, et al. (2016)
• A first-in-Asian phase 1 study to evaluate safety, pharmacokinetics and clinical activity of VS-6063, a focal adhesion kinase (FAK) inhibitor in Japanese patients with advanced solid tumors — T. Shimizu, K. Fukuoka, et al. (2016)
• E-cadherin, E-selectin and vascular cell adhesion molecule: immunohistochemical markers for differentiation between mesothelioma and metastatic pulmonary adenocarcinoma? — A.M. Müller, A. Weichert, et al. (2002)

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