Proteomic profiling reveals CDK6 upregulation as a targetable resistance mechanism for lenalidomide in multiple myeloma.

ATPases Associated with Diverse Cellular Activities / metabolism Cell Cycle Proteins / metabolism Cyclin-Dependent Kinase 6 / genetics Drug Resistance, Neoplasm Humans Immunologic Factors / pharmacology Lenalidomide / pharmacology Multiple Myeloma / drug therapy Neoplasm Recurrence, Local / drug therapy Proteomics Ubiquitin-Protein Ligases / metabolism Up-Regulation

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
23 02 2022
Historique:
received: 22 01 2021
accepted: 26 01 2022
entrez: 24 2 2022
pubmed: 25 2 2022
medline: 13 4 2022
Statut: epublish

Résumé

The immunomodulatory drugs (IMiDs) lenalidomide and pomalidomide are highly effective treatments for multiple myeloma. However, virtually all patients eventually relapse due to acquired drug resistance with resistance-causing genetic alterations being found only in a small subset of cases. To identify non-genetic mechanisms of drug resistance, we here perform integrated global quantitative tandem mass tag (TMT)-based proteomic and phosphoproteomic analyses and RNA sequencing in five paired pre-treatment and relapse samples from multiple myeloma patients. These analyses reveal a CDK6-governed protein resistance signature that includes myeloma high-risk factors such as TRIP13 and RRM1. Overexpression of CDK6 in multiple myeloma cell lines reduces sensitivity to IMiDs while CDK6 inhibition by palbociclib or CDK6 degradation by proteolysis targeting chimeras (PROTACs) is highly synergistic with IMiDs in vitro and in vivo. This work identifies CDK6 upregulation as a druggable target in IMiD-resistant multiple myeloma and highlights the use of proteomic studies to uncover non-genetic resistance mechanisms in cancer.

Identifiants

DOI: 10.1038/s41467-022-28515-1 PMID: 35197447 PMC: PMC8866544
pubmed: 35197447
doi: 10.1038/s41467-022-28515-1
pii: 10.1038/s41467-022-28515-1
pmc: PMC8866544
doi:

Substances chimiques

Cell Cycle Proteins 0
Immunologic Factors 0
Ubiquitin-Protein Ligases EC 2.3.2.27
CDK6 protein, human EC 2.7.11.22
Cyclin-Dependent Kinase 6 EC 2.7.11.22
ATPases Associated with Diverse Cellular Activities EC 3.6.4.-
TRIP13 protein, human EC 3.6.4.-
Lenalidomide F0P408N6V4

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1009

Informations de copyright

© 2022. The Author(s).

Références

Kumar, S. K., Rajkumar, V., Kyle, R. A., Van Duin, M. & Sonneveld, P. Multiple myeloma. Nat. Rev. Dis. Prim. 3, 1–20 (2017).
Ito, T. et al. Identification of a primary target of thalidomide teratogenicity. Science 327, 1345–1350 (2010).
pubmed: 20223979 doi: 10.1126/science.1177319
Krönke, J. et al. Lenalidomide causes selective degradation of IKZF1 and IKZF3 in multiple myeloma cells. Science 343, 301–305 (2014).
pubmed: 24292625 doi: 10.1126/science.1244851
Lu, G. et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of ikaros proteins. Science 343, 305–309 (2014).
pubmed: 24292623 doi: 10.1126/science.1244917
Zhu, Y. X. et al. Identification of cereblon-binding proteins and relationship with response and survival after IMiDs in multiple myeloma. Blood 124, 536–545 (2014).
pubmed: 24914135 pmcid: 4110660 doi: 10.1182/blood-2014-02-557819
Shaffer, A. L. et al. IRF4 addiction in multiple myeloma. Nature 454, 226–231 (2008).
pubmed: 18568025 pmcid: 2542904 doi: 10.1038/nature07064
Fischer, E. S. et al. Structure of the DDB1-CRBN E3 ubiquitin ligase in complex with thalidomide. Nature 512, 115–124 (2014).
doi: 10.1038/nature13527
Miguel, J. S. et al. Pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone alone for patients with relapsed and refractory multiple myeloma (MM-003): A randomised, open-label, phase 3 trial. Lancet Oncol. 14, 1055–1066 (2013).
pubmed: 24007748 doi: 10.1016/S1470-2045(13)70380-2
Kortüm, K. M. et al. Targeted sequencing of refractory myeloma reveals a high incidence of mutations in CRBN and Ras pathway genes. Blood 128, 1226–1233 (2016).
pubmed: 27458004 pmcid: 5524534 doi: 10.1182/blood-2016-02-698092
Barrio, S. et al. IKZF1/3 and CRL4-CRBN E3 ubiquitin ligase mutations and IMiD resistance in multiple myeloma. Haematologica 105, e240 (2020).
doi: 10.3324/haematol.2019.217943
Liu, J. et al. A genome-scale CRISPR-Cas9 screening in myeloma cells identifies regulators of immunomodulatory drug sensitivity. Leukemia 33, 171–180 (2019).
pubmed: 30026574 doi: 10.1038/s41375-018-0205-y
Lu, G. et al. UBE2G1 governs the destruction of cereblon neomorphic substrates. eLife 7, 1–24 (2018).
doi: 10.7554/eLife.40958
Sievers, Q. L., Gasser, J. A., Cowley, G. S., Fischer, E. S. & Ebert, B. L. Genome-wide screen identifies cullin-RING ligase machinery required for lenalidomide-dependent CRL4CRBN activity. Blood 132, 1293–1303 (2018).
pubmed: 30042095 pmcid: 6148446 doi: 10.1182/blood-2018-01-821769
Chavan, S. S. et al. Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J. 7, 1–7 (2017).
doi: 10.1038/bcj.2017.12
Weinhold, N. et al. Clonal selection and double-hit events involving tumor suppressor genes underlie relapse in myeloma. Blood 128, 1735–1744 (2016).
pubmed: 27516441 pmcid: 5043128 doi: 10.1182/blood-2016-06-723007
Lohr, J. G. et al. Widespread genetic heterogeneity in multiple myeloma: Implications for targeted therapy. Cancer Cell. 25, 91–101 (2014).
pubmed: 24434212 pmcid: 4241387 doi: 10.1016/j.ccr.2013.12.015
Bohl, S. R. et al. Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma. Blood Adv. 5, 2391–2402 (2021).
pubmed: 33950175 pmcid: 8114551 doi: 10.1182/bloodadvances.2020003541
Shaughnessy, J. D. et al. A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 109, 2276–2284 (2007).
pubmed: 17105813 doi: 10.1182/blood-2006-07-038430
Nair, B. et al. Gene expression profiling of plasma cells at myeloma relapse from tandem transplantation trial Total Therapy 2 predicts subsequent survival. Blood 113, 3572–3575 (2009).
doi: 10.1182/blood-2009-02-207803
Schwanhüusser, B. et al. Global quantification of mammalian gene expression control. Nature 473, 337–342 (2011).
doi: 10.1038/nature10098
Mertins, P. et al. Proteogenomics connects somatic mutations to signaling in breast cancer. Nature 534, 55–62 (2016).
pubmed: 27251275 pmcid: 5102256 doi: 10.1038/nature18003
Vasaikar, S. et al. Proteogenomic analysis of human colon cancer reveals new therapeutic opportunities. Cell 177, 1035–1049.e19 (2019).
pubmed: 31031003 pmcid: 6768830 doi: 10.1016/j.cell.2019.03.030
Zhang, H. et al. Integrated proteogenomic characterization of human high-grade serous ovarian cancer. Cell 166, 755–765 (2016).
pubmed: 27372738 pmcid: 4967013 doi: 10.1016/j.cell.2016.05.069
Morales, M. L. et al. MEK inhibition enhances the response to tyrosine kinase inhibitors in acute myeloid leukemia. Sci. Rep. 9, 18630 (2019).
pubmed: 31819100 pmcid: 6901485 doi: 10.1038/s41598-019-54901-9
Zaal, E. A. et al. Bortezomib resistance in multiple myeloma is associated with increased serine synthesis. Cancer Metab. 5, 1–12 (2017).
doi: 10.1186/s40170-017-0169-9
Dytfeld, D. et al. Comparative proteomic profiling of refractory/relapsed multiple myeloma reveals biomarkers involved in resistance to bortezomib-based therapy. Oncotarget 7, 56726–56736 (2016).
pubmed: 27527861 pmcid: 5302948 doi: 10.18632/oncotarget.11059
Eichner, R. et al. Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity. Nat. Med. 22, 735–743 (2016).
pubmed: 27294876 doi: 10.1038/nm.4128
Li, C. et al. TRIP13 modulates protein deubiquitination and accelerates tumor development and progression of B cell malignancies. J. Clin. Investig. 131, e146893 (2021).
Heuck, C. J. et al. Five gene probes carry most of the discriminatory power of the 70-gene risk model in multiple myeloma. Leukemia 28, 2410–2413 (2014).
pubmed: 25079174 pmcid: 4274609 doi: 10.1038/leu.2014.232
Tao, Y. et al. TRIP13 impairs mitotic checkpoint surveillance and is associated with poor prognosis in multiple myeloma. Oncotarget 8, 26718–26731 (2017).
pubmed: 28157697 pmcid: 5432292 doi: 10.18632/oncotarget.14957
Sagawa, M. et al. Ribonucleotide reductase catalytic subunit M1 (RRM1) as a novel therapeutic target in multiple myeloma. Clin. Cancer Res. 23, 5225–5237 (2017).
pubmed: 28442502 pmcid: 5581671 doi: 10.1158/1078-0432.CCR-17-0263
Huang, X. et al. Prolonged early G 1 arrest by selective CDK4/CDK6 inhibition sensitizes myeloma cells to cytotoxic killing through cell cycle-coupled loss of IRF4. Blood 120, 1095–1106 (2012).
pubmed: 22718837 pmcid: 3412331 doi: 10.1182/blood-2012-03-415984
Bellutti, F. et al. CDK6 antagonizes P53-induced responses during tumorigenesis. Cancer Discov. 8, 884–897 (2018).
pubmed: 29899063 pmcid: 6031305 doi: 10.1158/2159-8290.CD-17-0912
Leone, P. E. et al. Deletions of CDKN2C in multiple myeloma: biological and clinical implications. Clin. Cancer Res. 14, 6033–6041 (2008).
pubmed: 18829482 pmcid: 2581792 doi: 10.1158/1078-0432.CCR-08-0347
Hu, M. G. et al. CDK6 kinase activity is required for thymocyte development. Blood 117, 6120–6131 (2011).
pubmed: 21508411 pmcid: 3122937 doi: 10.1182/blood-2010-08-300517
Baughn, L. B. et al. A novel orally active small molecule potently induces G1 arrest in primary myeloma cells and prevents tumor growth by specific inhibition of cyclin-dependent kinase 4/6. Cancer Res. 66, 7661–7667 (2006).
pubmed: 16885367 doi: 10.1158/0008-5472.CAN-06-1098
Fry, D. W. et al. Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts. Mol. Cancer Ther. 3, 1427–1437 (2004).
pubmed: 15542782 doi: 10.1158/1535-7163.1427.3.11
Chen, N., Zhou, S. & Palmisano, M. Clinical Pharmacokinetics and Pharmacodynamics of Lenalidomide. Clin. Pharmacokinet. 56, 139–152 (2017).
pubmed: 27351179 doi: 10.1007/s40262-016-0432-1
Burslem, G. M. & Crews, C. M. Proteolysis-targeting chimeras as therapeutics and tools for biological discovery. Cell 181, 102–114 (2020).
pubmed: 31955850 pmcid: 7319047 doi: 10.1016/j.cell.2019.11.031
Brand, M. et al. Homolog-selective degradation as a strategy to probe the function of CDK6 in AML. Cell Chem. Biol. 26, 300–306.e9 (2019).
pubmed: 30595531 doi: 10.1016/j.chembiol.2018.11.006
Steinebach, C. et al. Systematic exploration of different E3 ubiquitin ligases: an approach towards potent and selective CDK6 degraders. Chem. Sci. 11, 3474–3486 (2020).
pubmed: 33133483 pmcid: 7552917 doi: 10.1039/D0SC00167H
Connell-Crowley, L., Harper, J. W. & Goodrich, D. W. Cyclin D1/Cdk4 regulates retinoblastoma protein-mediated cell cycle arrest by site-specific phosphorylation. Mol. Biol. Cell 8, 287–301 (1997).
pubmed: 9190208 pmcid: 276080 doi: 10.1091/mbc.8.2.287
Finn, R. S. et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 11, 1–13 (2009).
doi: 10.1186/bcr2419
Dempster, J. M. et al. Extracting biological insights from the project achilles genome-scale CRISPR screens in cancer cell lines. bioRxiv https://doi.org/10.1101/720243 (2019).
Blanchet, E. et al. E2F transcription factor-1 regulates oxidative metabolism. Nat. Cell Biol. 13, 1146–1154 (2011).
pubmed: 21841792 doi: 10.1038/ncb2309
Kollmann, K. et al. A kinase-independent function of CDK6 links the cell cycle to tumor angiogenesis. Cancer Cell 24, 167–181 (2013).
pubmed: 23948297 pmcid: 3743049 doi: 10.1016/j.ccr.2013.07.012
Anders, L. et al. A systematic screen for CDK4/6 substrates links FOXM1 phosphorylation to senescence suppression in cancer cells. Cancer Cell 20, 620–634 (2011).
pubmed: 22094256 pmcid: 3237683 doi: 10.1016/j.ccr.2011.10.001
Marine, J. C., Dawson, S. J. & Dawson, M. A. Non-genetic mechanisms of therapeutic resistance in cancer. Nat. Rev. Cancer 20, 743–756 (2020).
pubmed: 33033407 doi: 10.1038/s41568-020-00302-4
Janker, L. et al. Metabolic, anti-apoptotic and immune evasion strategies of primary human myeloma cells indicate adaptations to hypoxia. Mol. Cell. Proteom. 18, 936–953 (2019).
doi: 10.1074/mcp.RA119.001390
Mohamed, A. et al. Concurrent lipidomics and proteomics on malignant plasma cells from multiple myeloma patients: probing the lipid metabolome. PLoS ONE 15, 1–16 (2020).
doi: 10.1371/journal.pone.0227455
Nusinow, D. P. et al. Quantitative proteomics of the cancer cell line encyclopedia. Cell 180, 387–402.e16 (2020).
pubmed: 31978347 pmcid: 7339254 doi: 10.1016/j.cell.2019.12.023
Tyanova, S. et al. Proteomic maps of breast cancer subtypes. Nat. Commun. 7, 1–11 (2016).
doi: 10.1038/ncomms10259
Alfieri, C., Chang, L. & Barford, D. Mechanism for remodelling of the cell cycle checkpoint protein MAD2 by the ATPase TRIP13. Nature 559, 274–278 (2018).
pubmed: 29973720 pmcid: 6057611 doi: 10.1038/s41586-018-0281-1
Wang, Y. et al. A small-molecule inhibitor targeting TRIP13 suppresses multiple myeloma progression. Cancer Res. 80, 536–548 (2020).
pubmed: 31732653 doi: 10.1158/0008-5472.CAN-18-3987
Niida, H. et al. Essential role of Tip60-dependent recruitment of ribonucleotide reductase at DNA damage sites in DNA repair during G1 phase. Genes Dev. 24, 333–338 (2010).
pubmed: 20159953 pmcid: 2816732 doi: 10.1101/gad.1863810
Kato, J., Matsushime, H., Hiebert, S. W., Ewen, M. E. & Sherr, C. J. Direct binding of cyclin D to the retinoblastoma gene product (pRb) and pRb phosphorylation by the cyclin D-dependent kinase CDK4. Genes Dev. 7, 331–342 (1993).
pubmed: 8449399 doi: 10.1101/gad.7.3.331
Ewen, M. E. et al. Functional interactions of the retinoblastoma protein with mammalian D-type cyclins. Cell 73, 487–497 (1993).
pubmed: 8343202 doi: 10.1016/0092-8674(93)90136-E
Dowdy, S. F. et al. Physical interaction of the retinoblastoma protein with human D cyclins. Cell 73, 499–511 (1993).
pubmed: 8490963 doi: 10.1016/0092-8674(93)90137-F
Ely, S. et al. Mutually exclusive cyclin-dependent kinase 4/cyclin D1 and cyclin-dependent kinase 6/cyclin D2 pairing inactivates retinoblastoma protein and promotes cell cycle dysregulation in multiple myeloma. Cancer Res. 65, 11345–11353 (2005).
pubmed: 16357141 doi: 10.1158/0008-5472.CAN-05-2159
De Dominici, M. et al. Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs. Blood 135, 1560–1573 (2020).
pubmed: 32040545 pmcid: 7193186 doi: 10.1182/blood.2019003604
Placke, T. et al. Requirement for CDK6 in MLL-rearranged acute myeloid leukemia. Blood 124, 13–23 (2014).
pubmed: 24764564 pmcid: 4190617 doi: 10.1182/blood-2014-02-558114
Martinez-Soria, N. et al. The oncogenic transcription factor RUNX1/ETO corrupts cell cycle regulation to drive leukemic transformation. Cancer Cell 34, 626–642.e8 (2018).
pubmed: 30300583 pmcid: 6179967 doi: 10.1016/j.ccell.2018.08.015
Niesvizky, R. et al. Phase 1/2 study of cyclin-dependent kinase (CDK)4/6 inhibitor palbociclib (PD-0332991) with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. Leuk. Lymphoma 56, 3320–3328 (2015).
pubmed: 25813205 doi: 10.3109/10428194.2015.1030641
Petrylak, D. P. et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI). American Society of Clinical Oncology. 2020;Abstract:
Mertins, P. et al. Integrated proteomic analysis of post-translational modifications by serial enrichment. Nat. Methods 10, 634–637 (2013).
pubmed: 23749302 pmcid: 3943163 doi: 10.1038/nmeth.2518
Cox, J. & Mann, M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat. Biotechnol. 26, 1367–1372 (2008).
doi: 10.1038/nbt.1511 pubmed: 19029910
Udeshi, N. D. et al. Rapid and deep-scale ubiquitylation profiling for biology and translational research. Nat. Commun. 11, 359 (2020).
Ritchie, M. E. et al. Limma powers differential expression analyses for RNA-sequencing and microarray studies. Nucleic Acids Res. 43, e47 (2015).
pubmed: 25605792 pmcid: 4402510 doi: 10.1093/nar/gkv007
Hornbeck, P. V. et al. PhosphoSitePlus, 2014: mutations, PTMs and recalibrations. Nucleic Acids Res. 43, D512–D520 (2015).
pubmed: 25514926 doi: 10.1093/nar/gku1267
Perez-Riverol, Y. et al. The PRIDE database and related tools and resources in 2019: improving support for quantification data. Nucleic Acids Res. 47, D442–D450 (2019).
pubmed: 30395289 doi: 10.1093/nar/gky1106
Dobin, A. et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics 29, 15–21 (2013).
pubmed: 23104886 doi: 10.1093/bioinformatics/bts635
Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Tien Tzu Hsueh Pao/Acta Electron. Sin. 102, 15545–15550 (2005).
Ross, F. M. et al. Report from the European myeloma network on interphase FISH in multiple myeloma and related disorders. Haematologica 97, 1272–1277 (2012).
pubmed: 22371180 pmcid: 3409827 doi: 10.3324/haematol.2011.056176
Heckl, D. et al. Generation of mouse models of myeloid malignancy with combinatorial genetic lesions using CRISPR-Cas9 genome editing. Nat. Biotechnol. 32, 941–946 (2014).
pubmed: 24952903 pmcid: 4160386 doi: 10.1038/nbt.2951
Ianevski, A., Giri, A. K. & Aittokallio, T. SynergyFinder 2.0: visual analytics of multi-drug combination synergies. Nucleic Acids Res. 48, W488–W493 (2020).
pubmed: 32246720 pmcid: 7319457 doi: 10.1093/nar/gkaa216

Auteurs

Yuen Lam Dora Ng (YLD)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
ORCID: 0000-0001-7959-454X

Evelyn Ramberger (E)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany.
German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.
ORCID: 0000-0003-2760-2696

Stephan R Bohl (SR)

Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany.
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.

Anna Dolnik (A)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Christian Steinebach (C)

Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany.
ORCID: 0000-0001-5638-1955

Theresia Conrad (T)

Experimentelle Pharmakologie & Onkologie (EPO) Berlin-Buch GmbH, Berlin, Germany.

Sina Müller (S)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.

Oliver Popp (O)

Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Miriam Kull (M)

Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany.

Mohamed Haji (M)

Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany.

Michael Gütschow (M)

Department of Pharmaceutical & Medicinal Chemistry, Pharmaceutical Institute, University of Bonn, Bonn, Germany.

Hartmut Döhner (H)

Department of Internal Medicine III, Ulm University Hospital, Ulm, Germany.

Wolfgang Walther (W)

Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.

Ulrich Keller (U)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Experimental and Clinical Research Center, Charité Universitätsmedizin Berlin and Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.
ORCID: 0000-0002-8485-1958

Lars Bullinger (L)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany.
Berlin Institute of Health (BIH), Berlin, Germany.

Philipp Mertins (P)

Proteomics Platform, Max Delbrück Center for Molecular Medicine, Berlin, Germany. philipp.mertins@mdc-berlin.de.
Berlin Institute of Health (BIH), Berlin, Germany. philipp.mertins@mdc-berlin.de.
ORCID: 0000-0002-2245-528X

Jan Krönke (J)

Department of Hematology, Oncology and Cancer Immunology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. jan.kroenke@charite.de.
German Cancer Consortium (DKTK) partner site Berlin and German Cancer Research Center (DKFZ), Heidelberg, Germany. jan.kroenke@charite.de.
ORCID: 0000-0002-4649-0506

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines de transport › Protéines AAA › ATPases associated with diverse cellular activities › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines du cycle cellulaire › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › Proline-directed protein kinases › Kinases cyclines-dépendantes › Kinase-6 cycline-dépendante › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Résistance aux substances › Résistance aux médicaments antinéoplasiques › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Actions chimiques et utilisations › Actions pharmacologiques › Effets physiologiques des médicaments › Facteurs immunologiques › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Composés hétérocycliques › Composés hétérocycliques à cycles fusionnés › Composés hétérobicycliques › Isoindoles › Phtalimides › Lénalidomide › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Maladies du système immunitaire › Syndromes immunoprolifératifs › Paraprotéinémies › Myélome multiple › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Disciplines des sciences naturelles › Chimie › Biochimie › Protéomique › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Ligases › Ubiquitin-protein ligase complexes › Ubiquitin-protein ligases › Proteomic profiling reveals CDK6 upregulation...
questionsmedicales.fr › Phénomènes physiologiques › Phénomènes pharmacologiques et toxicologiques › Phénomènes pharmacologiques › Régulation positive › Proteomic profiling reveals CDK6 upregulation...