Abstract |
Overcoming drug resistance and targeting cancer stem cells remain challenges for curative cancer treatment. To investigate the role of microRNAs ( miRNAs) in regulating drug resistance and leukemic stem cell (LSC) fate, we performed global transcriptome profiling in treatment-naive chronic myeloid leukemia (CML) stem/progenitor cells and identified that miR-185 levels anticipate their response to ABL tyrosine kinase inhibitors (TKIs). miR-185 functions as a tumor suppressor: its restored expression impaired survival of drug-resistant cells, sensitized them to TKIs in vitro, and markedly eliminated long-term repopulating LSCs and infiltrating blast cells, conferring a survival advantage in preclinical xenotransplantation models. Integrative analysis with mRNA profiles uncovered PAK6 as a crucial target of miR-185, and pharmacological inhibition of PAK6 perturbed the RAS/MAPK pathway and mitochondrial activity, sensitizing therapy-resistant cells to TKIs. Thus, miR-185 presents as a potential predictive biomarker, and dual targeting of miR-185-mediated PAK6 activity and BCR-ABL1 may provide a valuable strategy for overcoming drug resistance in patients.
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Authors | Hanyang Lin, Katharina Rothe, Min Chen, Andrew Wu, Artem Babaian, Ryan Yen, Jonathan Zeng, Jens Ruschmann, Oleh I Petriv, Kieran O'Neill, Tobias Maetzig, David J H F Knapp, Naoto Nakamichi, Ryan Brinkman, Inanc Birol, Donna L Forrest, Carl Hansen, R Keith Humphries, Connie J Eaves, Xiaoyan Jiang |
Journal | Blood
(Blood)
Vol. 136
Issue 5
Pg. 596-609
(07 30 2020)
ISSN: 1528-0020 [Electronic] United States |
PMID | 32270193
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © 2020 by The American Society of Hematology. |
Chemical References |
- MIRN185 microRNA, human
- MicroRNAs
- Protein Kinase Inhibitors
- PAK6 protein, human
- p21-Activated Kinases
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Topics |
- Animals
- Drug Resistance, Neoplasm
(genetics)
- Gene Expression Regulation, Leukemic
(genetics)
- Heterografts
- Humans
- Leukemia, Myelogenous, Chronic, BCR-ABL Positive
(drug therapy, genetics, metabolism)
- Mice
- Mice, SCID
- MicroRNAs
(genetics, metabolism)
- Neoplastic Stem Cells
(metabolism, pathology)
- Protein Kinase Inhibitors
(therapeutic use)
- Signal Transduction
(physiology)
- p21-Activated Kinases
(genetics, metabolism)
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