The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM)

Our plain-English summary of The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM), by M.L. Yuen, L. Zhuang, E.M. Rath, et al (International Journal of Molecular Sciences, 2021).

The study

• Authors: M.L. Yuen, L. Zhuang, E.M. Rath, T. Yu, B. Johnson, K.H. Sarun, Y. Wang, S. Kao, A. Linton, C.J. Clarke, B.C. McCaughan, K. Takahashi, K. Lee, Y.Y. Cheng
• Journal: International Journal of Molecular Sciences
• Published: 2021;22(19)
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive malignancy with limited effective treatment options. Focal adhesion kinase (FAK) inhibitors have been shown to efficiently suppress MPM cell growth initially, with limited utility in the current clinical setting. In this study, we utilised a large collection of MPM cell lines and MPM tissue samples to study the role of E-cadherin (CDH1) and microRNA on the efficacy of FAK inhibitors in MPM. The immunohistochemistry (IHC) results showed that the majority of MPM FFPE samples exhibited either the absence of, or very low, E-cadherin protein expression in MPM tissue. We showed that MPM cells with high CDH1 mRNA levels exhibited resistance to the FAK inhibitor PND-1186. In summary, MPM cells that did not express CDH1 mRNA were sensitive to PND-1186, and MPM cells that retained CDH1 mRNA were resistant. A cell cycle analysis showed that PND-1186 induced cell cycle disruption by inducing the G2/M arrest of MPM cells. A protein-protein interaction study showed that EGFR is linked to the FAK pathway, and a target scan of the microRNAs revealed that microRNAs (miR-17, miR221, miR-222, miR137, and miR148) interact with EGFR 3'UTR. Transfection of MPM cells with these microRNAs sensitised the CHD1-expressing FAK-inhibitor-resistant MPM cells to the FAK inhibitor.

In plain English

This laboratory study came from the Asbestos Diseases Research Institute in Sydney. It used malignant pleural mesothelioma (MPM) cell lines and 82 stored MPM tissue samples. It did not study asbestos exposure. It tested how cells responded to the experimental FAK inhibitor drug PND-1186. Of 81 tissue samples that could be stained, 55 (68%) showed no E-cadherin protein and 26 showed low levels. All 11 MPM cell lines tested showed low or absent E-cadherin protein. In MPM cell lines only, higher activity of the E-cadherin gene (CDH1 mRNA) went along with greater resistance to the drug (Spearman's rho 0.6432). The drug concentration that left half the cells alive was 0.70 plus or minus 0.05 micromolar in MSTO cells and 24.86 plus or minus 3.91 micromolar in Ren cells. The drug made cells stall at the G2/M stage of cell division. Adding five microRNAs made the tested MPM cell lines more drug-sensitive, most clearly H28. The authors concluded that CDH1 mRNA in MPM cells is associated with PND-1186 resistance and that microRNAs can sensitise resistant cells. The drug and microRNA tests were done on cells in the laboratory, not in patients; the patient tissue samples were only stained for E-cadherin.

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 mesothelioma cell lines and archived tumour tissue samples, testing a FAK inhibitor drug and microRNAs
• Who was studied: 82 MPM tumour tissue samples (formalin-fixed, paraffin-embedded) and 18 cell lines, including purchased cell lines and primary MPM cell lines established at the Asbestos Diseases Research Institute. Comparison cells included an immortalised non-cancer mesothelial cell line (MeT-5A), lung, breast and gastric cancer cell lines, and normal skin fibroblasts. Ethics approval came from Concord Repatriation General Hospital, Australia. Collection dates were not given.
• Exposure: No asbestos exposure was studied. Cells were treated with the FAK inhibitor drug PND-1186. Some cells were first given (transfected with) candidate microRNAs: miR-17, miR-221, miR-222, miR-137 and miR-148.
• Main results:
  • Of 81 MPM tissue samples with enough tissue, 55 (68%) showed no E-cadherin protein and 26 showed low levels (5 to 20% of cells staining positive)
  • All 11 MPM cell lines tested by staining showed low or absent E-cadherin protein
  • In mesothelioma cell lines, CDH1 mRNA levels were positively correlated with PND-1186 IC50 values (higher mRNA, more drug needed): Spearman's rho 0.6432, p-value 1.554 times 10 to the minus 7
  • In non-mesothelioma cell lines there was a slight negative correlation, which the authors described as statistically but not clinically significant: Spearman's rho minus 0.5257, p-value 0.0009923
  • Compared with MeT-5A non-cancer mesothelial cells, the MPM cell lines Ren, 1157, 1137, 2174 and 2359 were relatively resistant to PND-1186, and these had high CDH1 mRNA levels
  • PND-1186 IC50 in Ren MPM cells was 24.86 plus or minus 3.91 micromolar, the highest of all cell lines listed. The table does not say what the plus-or-minus figure represents.
  • PND-1186 IC50 in MSTO MPM cells was 0.70 plus or minus 0.05 micromolar. The table does not say what the plus-or-minus figure represents.
  • In four MPM cell lines (MSTO-211H, H28, Ren, 1157), PND-1186 caused cells to arrest at the G2/M phase of the cell cycle. This was statistically significant compared with untreated controls (p = 0.0113).
  • All five candidate microRNAs made H28 MPM cells more sensitive to PND-1186. The effect was less pronounced in MSTO-211H, Ren and 1157 cells.
• The authors' conclusion: The authors concluded that the presence of CDH1 mRNA in MPM cells is associated with resistance to PND-1186, regardless of E-cadherin protein measured by staining. They also concluded that microRNAs can sensitise FAK-inhibitor-resistant MPM cells to the drug.
• Limitations the authors state:
  • The authors said the lack of detected E-cadherin protein might reflect the antibody binding a part of the protein not present in the samples
  • The data used for the correlations had few points
  • The authors said animal (pre-clinical) studies are still needed to investigate FAK inhibitors in MPM

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Immunohistochemistry, EGFR.

Related studies

• E-cadherin expression is correlated with focal adhesion kinase inhibitor resistance in Merlin-negative malignant mesothelioma cells — T. Kato, T. Sato, et al. (2017)
• 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)
• Dysregulated Expression of the MicroRNA miR-137 and Its Target YBX1 Contribute to the Invasive Characteristics of Malignant Pleural Mesothelioma — T.G. Johnson, K. Schelch, et al. (2018)
• Combination of a p53-activating CP-31398 and an MDM2 or a FAK inhibitor produces growth suppressive effects in mesothelioma with wild-type p53 genotype — B. Zhong, M. Shingyoji, et al. (2020)
• Tumor Suppressor microRNAs Contribute to the Regulation of PD-L1 Expression in Malignant Pleural Mesothelioma — S.C. Kao, Y.Y. Cheng, et al. (2017)

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