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Heterogeneous resistance to quizartinib in acute myeloid leukemia revealed by single-cell analysis
Catherine C Smith1,2, Amy Paguirigan3, Grace R Jeschke4
1Division of Hematology/Oncology and.
Abstract:
Genomic studies have revealed significant branching heterogeneity in cancer. Studies of resistance to tyrosine kinase inhibitor therapy have not fully reflected this heterogeneity because resistance in individual patients has been ascribed to largely mutually exclusive on-target or off-target mechanisms in which tumors either retain dependency on the target oncogene or subvert it through a parallel pathway. Using targeted sequencing from single cells and colonies from patient samples, we demonstrate tremendous clonal diversity in the majority of acute myeloid leukemia (AML) patients with activating FLT3 internal tandem duplication mutations at the time of acquired resistance to the FLT3 inhibitor quizartinib. These findings establish that clinical resistance to quizartinib is highly complex and reflects the underlying clonal heterogeneity of AML.
Insights
Acquired resistance to quizartinib in acute myeloid leukemia (AML) is complex. Single-cell sequencing reveals extensive clonal diversity, challenging simple resistance mechanisms in FLT3-mutated AML.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Cancer evolution is characterized by genomic heterogeneity.
- Resistance to tyrosine kinase inhibitors (TKIs) is often attributed to simplified on-target or off-target mechanisms.
- This overlooks the complexity of tumor adaptation during TKI therapy.
Purpose of the Study:
- To investigate the clonal architecture of acute myeloid leukemia (AML) at the time of acquired resistance to quizartinib.
- To understand the heterogeneity of resistance mechanisms in FLT3-mutated AML.
- To explore the role of clonal diversity in clinical resistance to FLT3 inhibitors.
Main Methods:
- Targeted sequencing of single cells and colonies from patient samples.
- Analysis of acute myeloid leukemia (AML) patient samples with activating FLT3 internal tandem duplication (ITD) mutations.
- Assessment of tumor heterogeneity at the time of acquired resistance to quizartinib.
Main Results:
- Demonstrated significant clonal diversity in the majority of acute myeloid leukemia (AML) patients.
- Identified extensive heterogeneity at the time of acquired resistance to quizartinib.
- Showcased the complexity of resistance mechanisms beyond simple on-target or off-target pathways.
Conclusions:
- Clinical resistance to quizartinib in FLT3-mutated AML is highly complex.
- Underlying clonal heterogeneity significantly contributes to acquired resistance.
- Future therapies must account for intra-tumor diversity in AML.
