학술논문
Deep PIM kinase substrate profiling reveals new rational co-therapeutic strategies for acute myeloid leukemia.
Document Type
Academic Journal
Author
Joglekar T; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Chin A; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Voskanian-Kordi A; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Seungchul B; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Raja A; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Rege A; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Huang W; University of Maryland, Baltimore, Baltimore, Maryland, United States.; Kane MA; University of Maryland, Baltimore, Maryland, United States.; Laiho M; Johns Hopkins University School of Medicine, Baltimore, Maryland, United States.; Webb T; Wildflower Biopharma, Inc., San Diego, California, United States.; Fan X; University of Maryland Greenebaum Comprehensive Cancer Center, Baltimore, Maryland, United States.; Rubenstein M; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Bieberich CJ; University of Maryland, Baltimore County, Baltimore, Maryland, United States.; Li X; University of Maryland, Baltimore County, Baltimore, Maryland, United States.
Source
Publisher: American Society of Hematology Country of Publication: United States NLM ID: 101698425 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2473-9537 (Electronic) Linking ISSN: 24739529 NLM ISO Abbreviation: Blood Adv Subsets: MEDLINE
Subject
Language
English
Abstract
Provirus integration site for Moloney murine leukemia virus (PIM) family serine/threonine kinases perform pro-tumorigenic functions in hematologic malignancies and solid tumors by phosphorylating substrates involved in tumor metabolism, cell survival, metastasis, inflammation, and immune cell invasion. However, a comprehensive understanding of PIM kinase functions is currently lacking. Multiple small molecule PIM kinase inhibitors are currently being evaluated as co-therapeutics in cancer patients. To further illuminate PIM kinase functions in cancer, we deeply profiled PIM1 substrates using the reverse in-gel kinase assay to identify downstream cellular processes targetable with small molecules. Pathway analyses of putative PIM substrates nominated RNA splicing and rRNA processing as PIM-regulated cellular processes. PIM inhibition elicited reproducible splicing changes in PIM-inhibitor-responsive acute myeloid leukemia (AML) cell lines. PIM inhibitors synergized with splicing modulators targeting splicing factor 3b subunit 1 (SF3B1) and serine-arginine protein kinase 1 (SRPK1) to kill AML cells. PIM inhibition also altered rRNA processing, and PIM inhibitors synergized with an RNA polymerase I inhibitor to kill AML cells and block AML tumor growth. These data demonstrate that deep kinase substrate knowledge can illuminate unappreciated kinase functions, nominating synergistic co-therapeutic strategies. This approach may expand the co-therapeutic armamentarium to overcome kinase-inhibitor resistant disease that limits durable responses in malignant disease.
(Copyright © 2024 American Society of Hematology.)
(Copyright © 2024 American Society of Hematology.)