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

Ng, Yuen Lam Dora; Ramberger, Evelyn; Bohl, Stephan R; Dolnik, Anna; Steinebach, Christian; Conrad, Theresia; Müller, Sina; Popp, Oliver; Kull, Miriam; Haji, Mohamed; Gütschow, Michael; Döhner, Hartmut; Walther, Wolfgang; Keller, Ulrich; Bullinger, Lars; Mertins, Philipp; Krönke, Jan

doi:10.1038/s41467-022-28515-1

Cited by 37 publications

(36 citation statements)

References 77 publications

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“…Notably, chr3 includes the proto-oncogene Nras , as well as Fam46c encoding a non-canonical poly(A) polymerase that is frequently mutated in MM and acts as a tumor suppressor for MM development [63, 64]. Chr5 includes Fgfr3 and Mmset , both of which are overexpressed in t(4;14) MM patients [12], and cyclin-dependent kinase 6 ( Cdk6 ) that was recently found to be over-expressed in immunomodulatory drug-resistant MM cells [65]. Finally, chr15 includes the transcription factor Myc , frequently dysregulated in MM [66].…”

Section: Resultsmentioning

confidence: 99%

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Flietner

Rajagopalan

et al. 2022

Preprint

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Multiple myeloma (MM) is a cancer of malignant plasma cells in the bone marrow and extramedullary sites. We previously characterized a VQ model for human high-risk MM. Different VQ lines display distinct disease phenotypes and survivals, suggesting significant intra-model variation. Here, we use whole exome sequencing and copy number variation (CNV) analysis coupled with RNA-Seq to stratify VQ lines into corresponding clusters: Cluster I VQ cells carried recurrent amplification of chromosome (chr) 3 and displayed upregulation of growth pathways and high-risk myeloma gene signatures, whereas Cluster II cells had monosomy chr5 and overexpressed genes and pathways associated with positive response to bortezomib (Btz) treatment in human MM patients. Consistently, in sharp contrast to Cluster II VQ cells that showed short-term response to Btz, Cluster I VQ cells were de novo resistant to Btz in vivo. Our study highlights Cluster I VQ lines as highly representative of human high-risk MM subset.

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Section: Resultsmentioning

confidence: 99%

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Flietner

Rajagopalan

et al. 2022

Preprint

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“…A recently published study performed integrated global quantitative tandem-mass-tag (TMT)-based proteomic and phosphoproteomic analyses in MM samples to identify a non-genetic resistance mechanism for IMiD that can be targeted by pharmacologic intervention. The results showed upregulation of CDK6, which appeared to decrease sensitivity to IMID [ 292 ]. Inhibition of CDK6 with palbociclib or degradation of CDK6 by PROTAC was found to be highly effective and synergistic with IMiD in pre-clinical in vivo and in vitro models [ 292 ].…”

Section: Emerging Approaches and Future Directionsmentioning

confidence: 99%

“…The results showed upregulation of CDK6, which appeared to decrease sensitivity to IMID [ 292 ]. Inhibition of CDK6 with palbociclib or degradation of CDK6 by PROTAC was found to be highly effective and synergistic with IMiD in pre-clinical in vivo and in vitro models [ 292 ]. These findings suggested further investigation of CDK6 as a potential drug target.…”

Section: Emerging Approaches and Future Directionsmentioning

confidence: 99%

Multiple Myeloma Therapy: Emerging Trends and Challenges

Dima

Jiang

Singh

et al. 2022

Cancers

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Multiple myeloma (MM) is a complex hematologic malignancy characterized by the uncontrolled proliferation of clonal plasma cells in the bone marrow that secrete large amounts of immunoglobulins and other non-functional proteins. Despite decades of progress and several landmark therapeutic advancements, MM remains incurable in most cases. Standard of care frontline therapies have limited durable efficacy, with the majority of patients eventually relapsing, either early or later. Induced drug resistance via up-modulations of signaling cascades that circumvent the effect of drugs and the emergence of genetically heterogeneous sub-clones are the major causes of the relapsed-refractory state of MM. Cytopenias from cumulative treatment toxicity and disease refractoriness limit therapeutic options, hence creating an urgent need for innovative approaches effective against highly heterogeneous myeloma cell populations. Here, we present a comprehensive overview of the current and future treatment paradigm of MM, and highlight the gaps in therapeutic translations of recent advances in targeted therapy and immunotherapy. We also discuss the therapeutic potential of emerging preclinical research in multiple myeloma.

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“…The next-generation PROTACs based on CRL4 CRBN —pomalidomide interaction also targets BET proteins (ARV 825), which showed promising activity against MM cells, including in vivo activity in a mice model [ 97 , 98 ]. Effective PROTACs targeting other MM promising oncoproteins such as CDK4 and CDK6 [ 99 , 100 ] and MCL-1 [ 101 ] have also been described.…”

Section: Proteolysis Targeting Chimeras (Protacs)mentioning

confidence: 99%

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

Barankiewicz

Salomon-Perzyński

Misiewicz-Krzemińska

et al. 2022

Cancers

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Multiple myeloma (MM) is the second most common hematological malignancy with a recurrent clinical course. The introduction of immunomodulatory drugs (IMiDs) was one of the milestones in MM therapy leading to a significant improvement in patients’ prognosis. Currently, IMiDs are the backbone of MM therapy in newly diagnosed and relapsed/refractory settings. It is now known that IMiDs exert their anti-myeloma activity mainly by binding cereblon (CRBN), the substrate receptor protein of the CRL4 E3 ubiquitin ligase (CRL4CRBN) complex. By binding CRBN, IMiDs alter its substrate specificity, leading to ubiquitination and proteasomal degradation of proteins essential for MM cell survival. Following the success of IMiDs, it is not surprising that the possibility of using the CRL4CRBN complex’s activity to treat MM is being further explored. In this review, we summarize the current state of knowledge about novel players in the MM therapeutic landscape, namely the CRBN E3 ligase modulators (CELMoDs), the next generation of IMiDs with broader biological activity. In addition, we discuss a new strategy of tailored proteolysis called proteolysis targeting chimeras (PROTACs) using the CRL4CRBN to degrade typically undruggable proteins, which may have relevance for the treatment of MM and other malignancies in the future.

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

Cited by 37 publications

References 77 publications

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Genomic and transcriptional profiling stratifies VQ myeloma lines into two clusters with distinct risk signatures and drug responses

Multiple Myeloma Therapy: Emerging Trends and Challenges

CRL4CRBN E3 Ligase Complex as a Therapeutic Target in Multiple Myeloma

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