Combined treatment with inhibitors of ErbB Receptors and Hh signaling pathways is more effective than single treatment in reducing the growth of malignant mesothelioma both in vitro and in vivo

• DOI: 10.1186/s12967-022-03490-9
• Publication Date: 2022-06-25T13:03:46Z
• Authors: Roberto Bei; Monica Benvenuto; Chiara Focaccetti; Sara Fazi; Marta Moretti; Daniela Nardozi; Valentina Angiolini; Sara Ciuffa; Loredana Cifaldi; Raffaele Carrano; Camilla Palumbo; Martino Tony Miele; Riccardo Bei; Giovanni Barillari; Vittorio Manzari; Enrico De Smaele; Andrea Modesti; Laura Masuelli
• Keywords: Mesothelioma; 570; 610; Afatinib; EGFR/ErbB receptors; GANT-61; Hedgehog/GLI pathway; malignant mesothelioma; Afatinib; Zinc Finger Protein GLI1; Cell Line; Settore MED/05 - PATOLOGIA CLINICA; Mice; 03 medical and health sciences; EGFR/ErbB receptors; Settore MED/04 - PATOLOGIA GENERALE; Cell Line, Tumor; GANT-61; Animals; Humans; Hedgehog Proteins; Malignant mesothelioma; Malignant; 0303 health sciences; Tumor; Research; Mesothelioma, Malignant; R; 3. Good health; ErbB Receptors; Hedgehog/GLI pathway; Medicine; Signal Transduction

AbstractMalignant mesothelioma (MM) is a rare orphan aggressive neoplasia with low survival rates. Among the other signaling pathways, ErbB receptors and Hh signaling are deregulated in MM. Thus, molecules involved in these signaling pathways could be used for targeted therapy approaches. The aim of this study was to evaluate the effects of inhibitors of Hh- (GANT-61) and ErbB receptors (Afatinib)-mediated signaling pathways, when used alone or in combination, on growth, cell cycle, cell death and autophagy, modulation of molecules involved in transduction pathways, in three human MM cell lines of different histotypes. The efficacy of the combined treatment was also evaluated in a murine epithelioid MM cell line both in vitro and in vivo. This study demonstrated that combined treatment with two inhibitors counteracting the activation of two different signaling pathways involved in neoplastic transformation and progression, such as those activated by ErbB and Hh signaling, is more effective than the single treatments in reducing MM growth in vitro and in vivo.This study may have clinical implications for the development of targeted therapy approaches for MM.