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Transitory dasatinib-resistant states in KIT(mut) t(8;21) acute myeloid leukemia cells correlate with altered KIT
Markus D Herrmann1, Jochen K Lennerz2, Lars Bullinger3
1Department of Pediatrics and Adolescent Medicine, University Medical Center, Ulm, Germany.
Abstract:
KIT inhibition with dasatinib represents a promising approach to targeted therapy in t(8;21) acute myeloid leukemia (AML) and clinical trials are currently evaluating its clinical relevance. However, data on continuous long-term dasatinib exposure of AML cells are limited and the potential effects on KIT inhibition and dasatinib sensitivity are unexplored. Treatment-related resistance ultimately limits clinical efficacy of tyrosine kinase inhibitors (TKI), which could similarly apply to dasatinib in t(8;21) AML. In this study, we used the dasatinib-sensitive KIT(mut) t(8;21) AML cell line Kasumi-1 to model, in a confined and controllable way, molecular effects upon continuous dasatinib treatment. Long-term dasatinib exposure at clinically relevant levels resulted in markedly decreased drug-sensitivity of KIT(mut) t(8;21) AML cells. Notably, all dasatinib-resistant clones lacked secondary KIT-mutations. Instead, persistent growth correlated with alterations in KIT expression levels-that is, either KIT overexpression with maintained downstream signaling or KIT downregulation with concomitant activation of alternate pathways. Although KIT overexpression was associated with retained receptor activity and STAT3 activation, KIT downregulation correlated with decreased STAT3 levels and increased ERK-signaling. Importantly, brief discontinuation of dasatinib restored dasatinib-sensitivity associated with reversal of signaling signatures similar to treatment-naive, dasatinib-sensitive cells. The observed desensitization of KIT(mut) t(8;21) AML cells upon continuous dasatinib exposure suggests that therapy-related acquisition of resistance could pose significant limitations on therapeutic efficiency. Notably, we identified TKI-resistant states of transient nature that correlate with alterations in KIT expression and can be reversed upon brief inhibitor withdrawal. These findings indicate that discontinuing treatment maintains dasatinib sensitivity in KIT(mut) AML cells.
Insights
Continuous dasatinib treatment in acute myeloid leukemia (AML) can lead to resistance by altering KIT expression, not secondary mutations. Brief drug withdrawal can restore sensitivity, suggesting treatment holidays may maintain efficacy.
Area of Science:
- Hematology
- Oncology
- Molecular Biology
Background:
- Dasatinib is a promising targeted therapy for t(8;21) acute myeloid leukemia (AML) by inhibiting KIT.
- Limited data exist on long-term dasatinib exposure and its effects on KIT inhibition and drug sensitivity in AML.
- Acquired resistance to tyrosine kinase inhibitors (TKIs) is a significant clinical challenge.
Purpose of the Study:
- To investigate the molecular effects of continuous dasatinib exposure on KIT(mut) t(8;21) AML cells.
- To explore mechanisms of dasatinib resistance and sensitivity restoration in this AML subtype.
- To assess the impact of long-term treatment on KIT expression and downstream signaling.
Main Methods:
- Utilized the dasatinib-sensitive KIT(mut) t(8;21) AML cell line Kasumi-1 for continuous drug exposure experiments.
- Monitored changes in dasatinib sensitivity, KIT expression levels, and downstream signaling pathways (STAT3, ERK).
- Analyzed for secondary KIT mutations in dasatinib-resistant clones.
Main Results:
- Long-term dasatinib exposure significantly decreased drug sensitivity in KIT(mut) t(8;21) AML cells.
- Acquired resistance was not due to secondary KIT mutations but to altered KIT expression (overexpression or downregulation).
- KIT overexpression maintained signaling and activated STAT3; KIT downregulation activated ERK signaling.
- Brief discontinuation of dasatinib restored drug sensitivity and reversed signaling alterations.
Conclusions:
- Continuous dasatinib treatment can induce transient TKI resistance in KIT(mut) AML through KIT expression changes.
- Altered KIT expression, rather than secondary mutations, drives resistance.
- Intermittent dasatinib therapy may be a strategy to maintain drug sensitivity in t(8;21) AML.
