Frontiers in Oncology (Nov 2022)
Mutational analysis and protein profiling predict drug sensitivity in multiple myeloma cell lines
- Mariaserena Giliberto,
- Mariaserena Giliberto,
- Leonardo Miranda Santana,
- Leonardo Miranda Santana,
- Leonardo Miranda Santana,
- Toril Holien,
- Toril Holien,
- Toril Holien,
- Kristine Misund,
- Sigve Nakken,
- Sigve Nakken,
- Sigve Nakken,
- Daniel Vodak,
- Daniel Vodak,
- Daniel Vodak,
- Eivind Hovig,
- Eivind Hovig,
- Eivind Hovig,
- Leonardo A. Meza-Zepeda,
- Leonardo A. Meza-Zepeda,
- Leonardo A. Meza-Zepeda,
- Eivind Coward,
- Eivind Coward,
- Anders Waage,
- Anders Waage,
- Anders Waage,
- Kjetil Taskén,
- Kjetil Taskén,
- Sigrid S. Skånland,
- Sigrid S. Skånland
Affiliations
- Mariaserena Giliberto
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Mariaserena Giliberto
- K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Leonardo Miranda Santana
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Leonardo Miranda Santana
- K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Leonardo Miranda Santana
- Oslo Centre for Biostatistics and Epidemiology, University of Oslo, Oslo, Norway
- Toril Holien
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Toril Holien
- Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway
- Toril Holien
- Department of Immunology and Transfusion Medicine, St. Olav’s University Hospital, Trondheim, Norway
- Kristine Misund
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Sigve Nakken
- Norwegian Cancer Genomics Consortium, Oslo University Hospital, Oslo, Norway
- Sigve Nakken
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Sigve Nakken
- Centre for Cancer Cell Reprogramming, Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
- Daniel Vodak
- Norwegian Cancer Genomics Consortium, Oslo University Hospital, Oslo, Norway
- Daniel Vodak
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Daniel Vodak
- 0Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Eivind Hovig
- Norwegian Cancer Genomics Consortium, Oslo University Hospital, Oslo, Norway
- Eivind Hovig
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Eivind Hovig
- 1Center for Bioinformatics, Department of Informatics, University of Oslo, Oslo, Norway
- Leonardo A. Meza-Zepeda
- Norwegian Cancer Genomics Consortium, Oslo University Hospital, Oslo, Norway
- Leonardo A. Meza-Zepeda
- Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Leonardo A. Meza-Zepeda
- 0Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Eivind Coward
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Eivind Coward
- 2Bioinformatics Core Facility, Norwegian University of Science and Technology, Trondheim, Norway
- Anders Waage
- Department of Clinical and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
- Anders Waage
- Department of Hematology, St. Olav’s University Hospital, Trondheim, Norway
- Anders Waage
- Department of Immunology and Transfusion Medicine, St. Olav’s University Hospital, Trondheim, Norway
- Kjetil Taskén
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Kjetil Taskén
- K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Sigrid S. Skånland
- Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway
- Sigrid S. Skånland
- K.G. Jebsen Centre for B Cell Malignancies, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- DOI
- https://doi.org/10.3389/fonc.2022.1040730
- Journal volume & issue
-
Vol. 12
Abstract
IntroductionMultiple myeloma (MM) is a heterogeneous disease where cancer-driver mutations and aberrant signaling may lead to disease progression and drug resistance. Drug responses vary greatly, and there is an unmet need for biomarkers that can guide precision cancer medicine in this disease.MethodsTo identify potential predictors of drug sensitivity, we applied integrated data from drug sensitivity screening, mutational analysis and functional signaling pathway profiling in 9 cell line models of MM. We studied the sensitivity to 33 targeted drugs and their association with the mutational status of cancer-driver genes and activity level of signaling proteins.ResultsWe found that sensitivity to mitogen-activated protein kinase kinase 1 (MEK1) and phosphatidylinositol-3 kinase (PI3K) inhibitors correlated with mutations in NRAS/KRAS, and PI3K family genes, respectively. Phosphorylation status of MEK1 and protein kinase B (AKT) correlated with sensitivity to MEK and PI3K inhibition, respectively. In addition, we found that enhanced phosphorylation of proteins, including Tank-binding kinase 1 (TBK1), as well as high expression of B cell lymphoma 2 (Bcl-2), correlated with low sensitivity to MEK inhibitors.DiscussionTaken together, this study shows that mutational status and signaling protein profiling might be used in further studies to predict drug sensitivities and identify resistance markers in MM.
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