Mechanisms of chemoresistance in relapsed AMLpatients: towards efficacious precision medicine
Acutemyeloid leukemia (AML) remains a devastating disease with a 5-year survivalrate of less than 30%. AML treatment has undergone significant advances inrecent years, incorporating novel targeted therapies along with improvements inallogeneic bone marrow transplantation techniques. However, the standard ofcare remains cytarabine and anthracyclines, and the primary hindrance towardscurative treatment is the frequent emergence of anticancer drug resistance. Herein, we characterizedchemoresistance mechanisms in human leukemia cell lines in vitro and inspecimens derived from individual AML patients ex vivo. We further explored potential pre-clinical treatment strategies tosurmount chemoresistanceas well as attempted to implement these findings towards efficacious personalized medicine.
Todecipher the mechanisms underlying cytarabine resistance we establishedcytarabine-resistant sublines derived from human leukemia cells andcharacterized the expression of cytarabine transport and metabolism genes usingreal-time PCR and Western blot analyses. These analyses were followed by growthinhibition assays and isobologram analysis determining the sublines’sensitivity to the clinically approved drugs hydroxyurea (HU) andazidothymidine (AZT), compared to their parental cells.Cytarabine-resistant sublines displayed marked hypersensitivityto HU and AZT compared to parental cells. The HU and AZT combination exhibiteda synergistic growth inhibitory effect on leukemia cells and AML patient specimens,which was intensified upon acquisition of cytarabine resistance. These findingsestablish HU and AZT as a promising combination for the potential futuretreatment of relapsed and refractory AML.
Towardsthe translation of these findings to the clinical setting, we explored twocases of relapsed AML patients. We determined the expression levels of specificgenes mediating drug transport and metabolism, nucleotide biosynthesis, andapoptosis, to decipher the molecular mechanisms underlying intrinsic and/oracquired chemoresistance modalities in individual relapsed patients. Thisanalysis revealed pre-existing differences in gene expression levels betweenthese relapsed patients and patients with lasting remissions following the sametreatment, as well as drug-induced alterations at different relapse stagescompared to diagnosis.
Ourfindings highlight the burning need for standardized evaluation of key drugtransport and metabolism genes as an integral component of routine AMLmanagement, thereby allowing for the tailoring of treatment regimens forindividual patients. This approach could facilitate the design of efficaciouspersonalized treatment regimens, thereby reducing relapse rates of a notorious therapyrefractory disease.