Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models
Abstract The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their charac...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2024-03-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-024-57028-8 |
| _version_ | 1827310217136701440 |
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| author | Silvia La Monica Federica Vacondio Kamal Eltayeb Alessio Lodola Francesco Volta Martina Viglioli Francesca Ferlenghi Francesca Galvani Maricla Galetti Mara Bonelli Claudia Fumarola Andrea Cavazzoni Lisa Flammini Michela Verzè Roberta Minari Pier Giorgio Petronini Marcello Tiseo Marco Mor Roberta Alfieri |
| author_facet | Silvia La Monica Federica Vacondio Kamal Eltayeb Alessio Lodola Francesco Volta Martina Viglioli Francesca Ferlenghi Francesca Galvani Maricla Galetti Mara Bonelli Claudia Fumarola Andrea Cavazzoni Lisa Flammini Michela Verzè Roberta Minari Pier Giorgio Petronini Marcello Tiseo Marco Mor Roberta Alfieri |
| author_sort | Silvia La Monica |
| collection | DOAJ |
| description | Abstract The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their characterization is essential to find new strategies to overcome resistance. Ceramides are well-known regulators of apoptosis and are converted into glucosylceramides (GlcCer) by glucosylceramide synthase (GCS). A higher content of GlcCers was observed in lung pleural effusions from NSCLC patients and their role in osimertinib-resistance has not been documented. The aim of this study was to determine the therapeutic potential of inhibiting GCS in NSCLC EGFR-mutant models resistant to osimertinib in vitro and in vivo. Lipidomic analysis showed a significant increase in the intracellular levels of glycosylceramides, including GlcCers in osimertinib resistant clones compared to sensitive cells. In resistant cells, the GCS inhibitor PDMP caused cell cycle arrest, inhibition of 2D and 3D cell proliferation, colony formation and migration capability, and apoptosis induction. The intratumoral injection of PDMP completely suppressed the growth of OR xenograft models. This study demonstrated that dysregulation of ceramide metabolism is involved in osimertinib-resistance and targeting GCS may be a promising therapeutic strategy for patients progressed to osimertinib. |
| first_indexed | 2024-04-24T19:56:08Z |
| format | Article |
| id | doaj.art-8eb304e906fc460c924afda0b45c67be |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-24T19:56:08Z |
| publishDate | 2024-03-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-8eb304e906fc460c924afda0b45c67be2024-03-24T12:19:02ZengNature PortfolioScientific Reports2045-23222024-03-0114111510.1038/s41598-024-57028-8Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell modelsSilvia La Monica0Federica Vacondio1Kamal Eltayeb2Alessio Lodola3Francesco Volta4Martina Viglioli5Francesca Ferlenghi6Francesca Galvani7Maricla Galetti8Mara Bonelli9Claudia Fumarola10Andrea Cavazzoni11Lisa Flammini12Michela Verzè13Roberta Minari14Pier Giorgio Petronini15Marcello Tiseo16Marco Mor17Roberta Alfieri18Department of Medicine and Surgery, University of ParmaDepartment of Food and Drug, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Food and Drug, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Food and Drug, University of ParmaDepartment of Food and Drug, University of ParmaDepartment of Food and Drug, University of ParmaDepartment of Occupational and Environmental Medicine, Epidemiology and Hygiene, INAIL-Italian Workers’ Compensation AuthorityDepartment of Medicine and Surgery, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Food and Drug, University of ParmaMedical Oncology Unit, University Hospital of ParmaMedical Oncology Unit, University Hospital of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Medicine and Surgery, University of ParmaDepartment of Food and Drug, University of ParmaDepartment of Medicine and Surgery, University of ParmaAbstract The EGFR tyrosine kinase inhibitor osimertinib has been approved for the first-line treatment of EGFR-mutated Non-Small Cell Lung Cancer (NSCLC) patients. Despite its efficacy, patients develop resistance. Mechanisms of resistance are heterogeneous and not fully understood, and their characterization is essential to find new strategies to overcome resistance. Ceramides are well-known regulators of apoptosis and are converted into glucosylceramides (GlcCer) by glucosylceramide synthase (GCS). A higher content of GlcCers was observed in lung pleural effusions from NSCLC patients and their role in osimertinib-resistance has not been documented. The aim of this study was to determine the therapeutic potential of inhibiting GCS in NSCLC EGFR-mutant models resistant to osimertinib in vitro and in vivo. Lipidomic analysis showed a significant increase in the intracellular levels of glycosylceramides, including GlcCers in osimertinib resistant clones compared to sensitive cells. In resistant cells, the GCS inhibitor PDMP caused cell cycle arrest, inhibition of 2D and 3D cell proliferation, colony formation and migration capability, and apoptosis induction. The intratumoral injection of PDMP completely suppressed the growth of OR xenograft models. This study demonstrated that dysregulation of ceramide metabolism is involved in osimertinib-resistance and targeting GCS may be a promising therapeutic strategy for patients progressed to osimertinib.https://doi.org/10.1038/s41598-024-57028-8 |
| spellingShingle | Silvia La Monica Federica Vacondio Kamal Eltayeb Alessio Lodola Francesco Volta Martina Viglioli Francesca Ferlenghi Francesca Galvani Maricla Galetti Mara Bonelli Claudia Fumarola Andrea Cavazzoni Lisa Flammini Michela Verzè Roberta Minari Pier Giorgio Petronini Marcello Tiseo Marco Mor Roberta Alfieri Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models Scientific Reports |
| title | Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models |
| title_full | Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models |
| title_fullStr | Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models |
| title_full_unstemmed | Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models |
| title_short | Targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib-resistant NSCLC cell models |
| title_sort | targeting glucosylceramide synthase induces antiproliferative and proapoptotic effects in osimertinib resistant nsclc cell models |
| url | https://doi.org/10.1038/s41598-024-57028-8 |
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