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

Abstract
Objectives: Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited treatment options, highlighting the need for the development of targeted therapies based on the tumor’s molecular phenotype. Additionally, there is a critical need to identify predictive biomarkers to better assess treatment responses.

Materials and Methods: The effects of various inhibitors were evaluated by assessing cell viability in primary MPM cell lines, which were established from patient tumors and thoroughly characterized at the molecular level. We also examined the impact of verteporfin on apoptosis, cell proliferation, and viability in multicellular spheroid cultures of MPM. To explore the mechanism of inhibition and identify specific predictive biomarkers, we utilized gene and protein expression analysis and gene knockdown via RNA interference.

Results: We investigated the anti-tumor effects of eight major signaling pathway inhibitors involved in mesothelial carcinogenesis. Three inhibitors showed greater efficacy than cisplatin, the standard first-line chemotherapy for MPM: verteporfin (a potential YAP inhibitor), defactinib (a FAK inhibitor), and NSC668394 (an Ezrin inhibitor). Among these, verteporfin was the most effective, inducing cell proliferation arrest and cell death, and demonstrating activity in a 3D spheroid model. Notably, verteporfin sensitivity was independent of YAP and correlated with the molecular classification of the tumors. We identified gene expression-based biomarkers that accurately predicted the tumors’ response to these inhibitors.

Conclusion: This study demonstrates that drug screening using well-characterized MPM cell models can uncover promising new therapeutic strategies and help identify biomarkers predictive of treatment Defactinib response.