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HDAC inhibitor AR-42 decreases CD44 expression and sensitizes myeloma cells to lenalidomide
Alessandro Canella1, Hector Cordero Nieves1, Douglas W Sborov2
1Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Abstract:
Multiple myeloma (MM) is a hematological malignancy of plasma cells in the bone marrow. Despite multiple treatment options, MM is inevitably associated with drug resistance and poor outcomes. Histone deacetylase inhibitors (HDACi's) are promising novel chemotherapeutics undergoing evaluation in clinical trials for the potential treatment of patients with MM. Although in preclinical studies HDACi's have proven anti-myeloma activity, but in the clinic single-agent HDACi treatments have been limited due to low tolerability. Improved clinical outcomes were reported only when HDACi's were combined with other drugs. Here, we show that a novel pan-HDACi AR-42 downregulates CD44, a glycoprotein that has been associated with lenalidomide and dexamethasone resistance in myeloma both in vitro and in vivo. We also show that this CD44 downregulation is in part mediated by miR-9-5p, targeting insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), which directly binds to CD44 mRNA and increases its stability. Importantly, we also demonstrate that AR-42 enhances anti-myeloma activity of lenalidomide in primary MM cells isolated from lenalidomide resistant patients and in in vivo MM mouse model. Thus, our findings shed light on potential novel combinatorial therapeutic approaches modulating CD44 expression, which may help overcome lenalidomide resistance in myeloma patients.
Insights
A novel drug, AR-42, downregulates CD44, a marker linked to multiple myeloma (MM) drug resistance. This approach enhances lenalidomide
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Multiple myeloma (MM) is a bone marrow cancer with inevitable drug resistance and poor outcomes.
- Histone deacetylase inhibitors (HDACi's) show preclinical anti-myeloma activity but have low tolerability as single agents.
- Combinatorial therapies with HDACi's improve clinical outcomes in MM treatment.
Purpose of the Study:
- To investigate the anti-myeloma effects of a novel pan-HDAC inhibitor, AR-42.
- To determine if AR-42 can overcome drug resistance in multiple myeloma.
- To elucidate the molecular mechanisms underlying AR-42's effects on CD44 expression.
Main Methods:
- Preclinical studies using in vitro and in vivo multiple myeloma models.
- Analysis of CD44 expression modulation by AR-42.
- Investigation of the role of miR-9-5p and IGF2BP3 in AR-42-mediated CD44 downregulation.
- Assessment of AR-42 in combination with lenalidomide in primary MM cells and a mouse model.
Main Results:
- AR-42 downregulates CD44, a glycoprotein associated with lenalidomide and dexamethasone resistance in MM.
- CD44 downregulation is partly mediated by miR-9-5p targeting IGF2BP3, which stabilizes CD44 mRNA.
- AR-42 enhances the anti-myeloma activity of lenalidomide in lenalidomide-resistant MM patient cells and an in vivo mouse model.
Conclusions:
- AR-42 demonstrates potential as a therapeutic agent for multiple myeloma.
- Modulating CD44 expression via AR-42 may offer a novel strategy to overcome lenalidomide resistance.
- Combinatorial therapy involving AR-42 and lenalidomide shows promise for treating resistant MM.
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