Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach
| العنوان: | Identification of relevant drugable targets in diffuse large B-cell lymphoma using a genome-wide unbiased CD20 guilt-by association approach |
|---|---|
| المؤلفون: | Edo Vellenga, Emanuele Ammatuna, Gerwin Huls, Lydia Visser, Rozemarijn S. van Rijn, Anke van den Berg, Rudolf S N Fehrmann, Mathilde Rikje Willemijn de Jong, Tom van Meerten, Arjan Diepstra, Marcel A. T. M. van Vugt |
| المساهمون: | Stem Cell Aging Leukemia and Lymphoma (SALL), Damage and Repair in Cancer Development and Cancer Treatment (DARE), Guided Treatment in Optimal Selected Cancer Patients (GUTS) |
| المصدر: | PLoS ONE, 13(2):e0193098. PUBLIC LIBRARY SCIENCE PLOS ONE PLoS ONE, Vol 13, Iss 2, p e0193098 (2018) PLoS ONE |
| بيانات النشر: | Public Library of Science (PLoS), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, Oncology, B Cells, Cancer Treatment, Poly (ADP-Ribose) Polymerase-1, Gene Expression, lcsh:Medicine, Cell Cycle Proteins, Genome-wide association study, CHOP, Biochemistry, IMPAIR ANTITUMOR-ACTIVITY, White Blood Cells, 0302 clinical medicine, Animal Cells, immune system diseases, hemic and lymphatic diseases, Antineoplastic Combined Chemotherapy Protocols, Medicine and Health Sciences, lcsh:Science, ANTI-CD20 MONOCLONAL-ANTIBODIES, Cancers and neoplasms, CD20, Multidisciplinary, biology, Pharmaceutics, Nuclear Proteins, Diffuse large B-cell lymphoma, Hematology, Protein-Tyrosine Kinases, CANCER, Neoplasm Proteins, 3. Good health, Nucleic acids, Cell killing, Vincristine, 030220 oncology & carcinogenesis, Lymphomas, Female, Rituximab, Lymphoma, Large B-Cell, Diffuse, Cellular Types, Research Article, medicine.drug, EXPRESSION, medicine.medical_specialty, Immune Cells, Immunology, DNA repair, 03 medical and health sciences, Drug Therapy, Cell Line, Tumor, Internal medicine, DNA-binding proteins, Genetics, medicine, Chemotherapy, Humans, NON-HODGKINS-LYMPHOMA, RITUXIMAB, Antibody-Producing Cells, Cyclophosphamide, Blood Cells, RECEPTOR, business.industry, lcsh:R, Biology and Life Sciences, Proteins, Cell Biology, DNA, Antigens, CD20, medicine.disease, Lymphoma, WEE1 KINASE, 030104 developmental biology, Doxorubicin, Drug Resistance, Neoplasm, Hematologic cancers and related disorders, biology.protein, Prednisone, lcsh:Q, INHIBITORS, business, Genome-Wide Association Study |
| الوصف: | Forty percent of patients with diffuse large B-cell lymphoma (DLBCL) show resistant disease to standard chemotherapy (CHOP) in combination with the anti-CD20 monoclonal antibody rituximab (R). Although many new anti-cancer drugs were developed in the last years, it is unclear which of these drugs can be safely combined to improve standard therapy without antagonizing anti-CD20 efficacy. In this study, we aimed to identify rituximab compatible drug-target combinations for DLBCL. For this, we collected gene expression profiles of 1,804 DLBCL patient samples. Subsequently, we performed a guilt-by-association analysis with MS4A1 (CD20) and prioritized the 500 top-ranked CD20-associated gene probes for drug-target interactions. This analysis showed the well-known genes involved in DLBCL pathobiology, but also revealed several genes that are relatively unknown in DLBCL, such as WEE1 and PARP1. To demonstrate potential clinical relevance of these targets, we confirmed high protein expression of WEE1 and PARP1 in patient samples. Using clinically approved WEE1 and PARP1 inhibiting drugs in combination with rituximab, we demonstrated significantly improved DLBCL cell killing, also in rituximab-insensitive cell lines. In conclusion, as exemplified by WEE1 and PARP1, our CD20-based genome-wide analysis can be used as an approach to identify biological relevant drug-targets that are rituximab compatible and may be implemented in phase 1/2 clinical trials to improve DLBCL treatment. |
| وصف الملف: | application/pdf |
| تدمد: | 1932-6203 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::63c3b212366b459c5bf23907c4ae6844Test https://doi.org/10.1371/journal.pone.0193098Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....63c3b212366b459c5bf23907c4ae6844 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 19326203 |
|---|