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Generation and Expansion of Primary, Malignant Pleural Mesothelioma Tumor Lines
Published on: April 21, 2022
The Role of E-Cadherin and microRNA on FAK Inhibitor Response in Malignant Pleural Mesothelioma (MPM)
Man Lee Yuen1, Ling Zhuang1, Emma M Rath2,3
1Asbestos Diseases Research Institute, Sydney, NSW 2139, Australia.
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.
Insights
E-cadherin (CDH1) expression dictates malignant pleural mesothelioma (MPM) cell response to focal adhesion kinase (FAK) inhibitors. Suppressing CDH1 or using specific microRNAs can sensitize resistant MPM cells to FAK inhibitors like PND-1186.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Malignant pleural mesothelioma (MPM) is an aggressive cancer with few treatment options.
- Focal adhesion kinase (FAK) inhibitors show initial promise but have limited clinical utility in MPM.
- The role of E-cadherin (CDH1) and microRNAs in FAK inhibitor efficacy requires further investigation.
Purpose of the Study:
- To investigate the impact of E-cadherin (CDH1) expression and microRNAs on FAK inhibitor efficacy in MPM.
- To identify mechanisms of resistance and potential strategies to overcome it.
Main Methods:
- Utilized a large collection of MPM cell lines and tissue samples.
- Performed immunohistochemistry (IHC) for E-cadherin protein expression.
- Assessed FAK inhibitor (PND-1186) sensitivity based on CDH1 mRNA levels.
- Conducted cell cycle analysis and protein-protein interaction studies.
- Investigated microRNA interactions with the EGFR pathway.
Main Results:
- Most MPM samples showed low or absent E-cadherin protein expression.
- MPM cells with high CDH1 mRNA levels were resistant to PND-1186, while those lacking CDH1 mRNA were sensitive.
- PND-1186 induced G2/M cell cycle arrest in MPM cells.
- EGFR was linked to the FAK pathway, and specific microRNAs (miR-17, miR221, miR222, miR137, miR148) target EGFR.
- Transfecting resistant MPM cells with these microRNAs sensitized them to PND-1186.
Conclusions:
- CDH1 mRNA expression is a key determinant of FAK inhibitor sensitivity in MPM.
- EGFR and specific microRNAs represent potential therapeutic targets to enhance FAK inhibitor efficacy in resistant MPM.
- Targeting the FAK pathway in conjunction with modulating CDH1 or microRNA levels may offer new treatment strategies for MPM.
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