ArticleSignal transduction and targeted therapy2025
Src inhibition potentiates MCL-1 antagonist activity in acute myeloid leukemia.
Article in Signal transduction and targeted therapy, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.
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Who cites it
7 citing papers in PubMed.
- Cyclin-Dependent Kinase 5 Contributes to Bruton's Tyrosine Kinase Inhibitor Resistance via the IRE1α/XBP1 Axis in Mantle Cell Lymphoma.Research square · 2026Article
- SRC as a Prognostic and Immunomodulatory Biomarker in Acute Myeloid Leukemia: A Multi-Omics Study.International journal of molecular sciences · 2026Article
- Targeting cell death pathways in acute myeloid leukemia: Molecular mechanisms and clinical implications (Review).Oncology reports · 2025Review
- Targeting the BCL2 Family: Advances and Challenges in BH3 Mimetic-Based Therapies.International journal of molecular sciences · 2025Review
- Review
- (R)-WAC-224, a new anticancer quinolone, combined with venetoclax and azacitidine overcomes venetoclax-resistant AML through MCL-1 downregulation.Scientific reports · 2025Article
- Ubiquitination regulation of mitochondrial homeostasis: a new sight for the treatment of gastrointestinal tumors.Frontiers in immunology · 2025Review
Corrections and comments
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Authors and funding
18 authors.
Funding
Abstract
The importance of MCL-1 in leukemogenesis has prompted development of MCL-1 antagonists e.g., S63845, MIK665. However, their effectiveness in acute myeloid leukemia (AML) is limited by compensatory MCL-1 accumulation via the ubiquitin proteasome system. Here, we investigated mechanisms by which kinase inhibitors with Src inhibitory activity e.g., bosutinib (SKI-606) might circumvent this phenomenon. MCL-1 antagonist/SKI-606 co-administration synergistically induced apoptosis in diverse AML cell lines. Consistently, Src or MCL-1 knockdown with shRNA markedly sensitized cells to MCL-1 inhibitors or SKI-606 respectively, while ectopic MCL-1 expression significantly diminished apoptosis. Mechanistically, MCL-1 antagonist exposure induced MCL-1 up-regulation, an event blocked by Src inhibitors or Src shRNA knock-down. MCL-1 down-regulation was associated with diminished transcription and increased K48-linked degradative ubiquitination. Enhanced cell death depended functionally upon down-regulation of phosphorylated STAT3 (Tyr705/Ser727) and cytoprotective downstream targets c-Myc and BCL-xL, as well as BAX/BAK activation, and NOXA induction. Importantly, the Src/MCL-1 inhibitor regimen robustly killed primary AML cells, including primitive progenitors, but spared normal hematopoietic CD34
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.