Enhanced sensitivity to glucocorticoids in cytarabine-resistant AML

Area of Science:

• Hematology
• Oncology
• Pharmacology

Background:

• Cytarabine is a key treatment for acute myeloid leukemia (AML).
• Acquired resistance to cytarabine poses a significant challenge in AML treatment.
• Mechanisms of cytarabine resistance and potential counteracting therapies require further investigation.

Purpose of the Study:

• To identify novel therapeutic strategies to overcome cytarabine resistance in acute myeloid leukemia (AML).
• To investigate the potential of emerging and clinical oncology compounds in resistant AML models and patient samples.

Main Methods:

• Generation of cytarabine-resistant AML cell lines (MOLM-13, SHI-1) through long-term drug exposure.
• Genomic and transcriptomic profiling of resistant cell lines and 66 ex vivo chemorefractory AML patient samples.
• High-throughput screening of 250 oncology compounds against resistant models and patient cells.

Main Results:

• Deletion of the deoxycytidine kinase (DCK) gene was identified in cytarabine-resistant variants and a patient sample.
• Cytarabine-resistant AML cells and a subset of patient samples exhibited enhanced sensitivity to glucocorticoids.
• Glucocorticoid sensitivity was acquired during AML relapse and was associated with wild-type FLT3 status (P=0.0006).

Conclusions:

• Cytarabine resistance in a subset of AML is associated with increased sensitivity to glucocorticoids.
• Glucocorticoids represent a potential therapeutic strategy for FLT3-wildtype, chemorefractory AML patients.
• Clinical trials are warranted to explore glucocorticoid-based therapies in this specific AML patient population.