Selective inhibition of Ph-positive ALL cell growth through kinase-dependent and -independent effects by CDK6-specific PROTACs
Open accessAbstract
Expression of the cell cycle regulatory gene CDK6 is required for Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL) cell growth, whereas expression of the closely related CDK4 protein is dispensable. Moreover, CDK6 silencing is more effective than treatment with the dual CDK4/6 inhibitor palbociclib in suppressing Ph+ ALL in mice, suggesting that the growth-promoting effects of CDK6 are, in part, kinase-independent in Ph+ ALL. Accordingly, we developed CDK4/6–targeted proteolysis-targeting chimeras (PROTACs) that inhibit CDK6 enzymatic activity in vitro, promote the rapid and preferential degradation of CDK6 over CDK4 in Ph+ ALL cells, and markedly suppress S-phase cells concomitant with inhibition of CDK6-regulated phospho-RB and FOXM1 expression. No such effects were observed in CD34+ normal hematopoietic progenitors, although CDK6 was efficiently degraded. Treatment with the CDK6-degrading PROTAC YX-2-107 markedly suppressed leukemia burden in mice injected with de novo or tyrosine kinase inhibitor–resistant primary Ph+ ALL cells, and this effect was comparable or superior to that of the CDK4/6 enzymatic inhibitor palbociclib. These studies provide “proof of principle” that targeting CDK6 with PROTACs that inhibit its enzymatic activity and promote its degradation represents an effective strategy to exploit the “CDK6 dependence” of Ph+ ALL and, perhaps, of other hematologic malignancies. Moreover, they suggest that treatment of Ph+ ALL with CDK6-selective PROTACs would spare a high proportion of normal hematopoietic progenitors, preventing the neutropenia induced by treatment with dual CDK4/6 inhibitors.
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Multiple types of leukemia cells are dependent on CDK6 for survival, including MLL and Ph+ ALL.
“Multiple types of leukemia cells are dependent on CDK6 for survival, including mixed-lineage leukemia (MLL) [123] and Philadelphia chromosome-positive ALL (Ph+ ALL) [9].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [9]
Selectively targeting CDK6 with ATP-competitive SMIs has been challenging due to identical ATP-binding domain in CDK4.
“However, selectively targeting CDK6 with ATP-competitive SMIs has been challenging due to the presence of an identical ATP-binding domain in its close-related homology CDK4 [9].”
From Proteolysis targeting chimeras (PROTACs) are emerging therapeutics for hematologic malignancies (2020) · cites this paper as [9]
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- Authors
- De Dominici, M., Porazzi, P., Xiao, Y., Chao, A., Tang, H.-Y., Kumar, G., Fortina, P., Spinelli, O., Rambaldi, A., Peterson, L. F., Petruk, S., Barletta, C., Mazo, A., Cingolani, G., Salvino, J. M., & Calabretta, B.
- Affiliations
- Department of Cancer Biology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA;
- Thomas Jefferson University (US)
- The Wistar Institute, Philadelphia, PA;
- The Wistar Institute (US)
- Ospedale Papa Giovanni XXIII (IT)
- University of Milan (IT)
- University of Michigan (US)
- Corresponding author
- Porazzi, Patrizia
- ORCID
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2020-04-30
- Volume
- 135
- Issue
- 18
- Pages
- 1560-1573
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- PMC
- PMC7193186
- OpenAlex
- W3006101943
- Cited by
- 94
- References
- 45
- Citations by year
- 2026: 8 · 2025: 20 · 2024: 12 · 2023: 7 · 2022: 24 · 2021: 15 · 2020: 7 · 2019: 1
- FWCI
- 4.38
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Blood (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- IRIS UNIMORE (University of Modena and Reggio Emilia) (submittedVersion, cc-by)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion)
- Funders
- National Heart, Lung, and Blood Institute (R01HL127895)
- National Cancer Institute (R01CA167169, R50CA221838, T32CA009171, P30CA056036, P30CA010815)
- National Institute of General Medical Sciences (R01GM122844)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Degradation and Inhibitors
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Acute Lymphoblastic Leukemia research
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Keywords
- Philadelphia chromosome-positive acute lymphoblastic leukemia, CDK6, PROTACs, CDK4/6 inhibitors, palbociclib, retinoblastoma protein phosphorylation, FOXM1, tyrosine kinase inhibitor resistance, neutropenia, leukemia cell proliferation
- MeSH terms
- Animals, Cell Cycle, Disease Models, Animal, Enzyme Activation, Humans, Phosphorylation, Recombinant Fusion Proteins, Molecular Structure, Treatment Outcome, Apoptosis, Genes, cdc, Gene Expression Profiling, Xenograft Model Antitumor Assays, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, Cyclin-Dependent Kinase 6, Mice, Precursor Cell Lymphoblastic Leukemia-Lymphoma
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