| Literature DB >> 32270193 |
Hanyang Lin1,2, Katharina Rothe1,3, Min Chen1, Andrew Wu1,2, Artem Babaian1,3, Ryan Yen1,2, Jonathan Zeng1, Jens Ruschmann1, Oleh I Petriv4,5, Kieran O'Neill1, Tobias Maetzig1, David J H F Knapp1,2, Naoto Nakamichi1, Ryan Brinkman1,3, Inanc Birol3,6, Donna L Forrest2,7, Carl Hansen4, R Keith Humphries1,2, Connie J Eaves1,2,3, Xiaoyan Jiang1,2,3.
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.Entities:
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Year: 2020 PMID： 32270193 PMCID： PMC7485576 DOI： 10.1182/blood.2019003636
Source DB: PubMed Journal: Blood ISSN： 0006-4971 Impact factor: 22.113