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Direct reversal of glucocorticoid resistance by AKT inhibition in acute lymphoblastic leukemia
Erich Piovan1,2,3, Jiyang Yu4,5, Valeria Tosello1,6
1Institute for Cancer Genetics, Columbia University, New York, NY, 10032, USA.
Abstract:
Glucocorticoid resistance is a major driver of therapeutic failure in T cell acute lymphoblastic leukemia (T-ALL). Here, we identify the AKT1 kinase as a major negative regulator of the NR3C1 glucocorticoid receptor protein activity driving glucocorticoid resistance in T-ALL. Mechanistically, AKT1 impairs glucocorticoid-induced gene expression by direct phosphorylation of NR3C1 at position S134 and blocking glucocorticoid-induced NR3C1 translocation to the nucleus. Moreover, we demonstrate that loss of PTEN and consequent AKT1 activation can effectively block glucocorticoid-induced apoptosis and induce resistance to glucocorticoid therapy. Conversely, pharmacologic inhibition of AKT with MK2206 effectively restores glucocorticoid-induced NR3C1 translocation to the nucleus, increases the response of T-ALL cells to glucocorticoid therapy, and effectively reverses glucocorticoid resistance in vitro and in vivo.
Insights
AKT1 kinase promotes glucocorticoid resistance in T cell acute lymphoblastic leukemia (T-ALL) by inhibiting the glucocorticoid receptor (NR3C1). Inhibiting AKT1 with MK2206 restores sensitivity to glucocorticoid therapy.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Glucocorticoid resistance is a significant challenge in treating T cell acute lymphoblastic leukemia (T-ALL).
- Understanding the molecular mechanisms underlying glucocorticoid resistance is crucial for developing effective therapies.
Purpose of the Study:
- To identify key regulators of glucocorticoid receptor (NR3C1) activity in T-ALL.
- To investigate the role of AKT1 kinase in mediating glucocorticoid resistance in T-ALL.
- To evaluate the therapeutic potential of AKT inhibition in overcoming glucocorticoid resistance.
Main Methods:
- Western blotting and immunoprecipitation to assess protein interactions and phosphorylation.
- Immunofluorescence microscopy to track NR3C1 nuclear translocation.
- Cell viability assays and apoptosis detection to measure drug response.
- In vitro and in vivo models of T-ALL treated with glucocorticoids and/or AKT inhibitors.
Main Results:
- AKT1 directly phosphorylates NR3C1 at S134, inhibiting its nuclear translocation and gene expression.
- Loss of PTEN leads to AKT1 activation, causing glucocorticoid resistance and blocking apoptosis.
- Pharmacologic inhibition of AKT with MK2206 restores NR3C1 nuclear translocation.
- MK2206 treatment reverses glucocorticoid resistance in T-ALL cells both in vitro and in vivo.
Conclusions:
- AKT1 is a critical negative regulator of NR3C1 activity and a driver of glucocorticoid resistance in T-ALL.
- Targeting AKT1 with inhibitors like MK2206 represents a promising strategy to re-sensitize T-ALL to glucocorticoid therapy.
- This study provides a mechanistic basis for combining AKT inhibitors with glucocorticoids for improved T-ALL treatment.
