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Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms

BEATAML1.0
BEATAML1.0-CRENOLANIB

Nature Communications. Volume 10, Issue 1 p.244, 16 January 2019; 10.1038/s41467-018-08263-x

FLT3 mutations are prevalent in AML patients and confer poor prognosis. Crenolanib, a potent type I pan-FLT3 inhibitor, is effective against both internal tandem duplications and resistance-conferring tyrosine kinase domain mutations. While crenolanib monotherapy has demonstrated clinical benefit in heavily pretreated relapsed/refractory AML patients, responses are transient and relapse eventually occurs. Here, to investigate the mechanisms of crenolanib resistance, we perform whole exome sequencing of AML patient samples before and after crenolanib treatment. Unlike other FLT3 inhibitors, crenolanib does not induce FLT3 secondary mutations, and mutations of the FLT3 gatekeeper residue are infrequent. Instead, mutations of NRAS and IDH2 arise, mostly as FLT3-independent subclones, while TET2 and IDH1 predominantly co-occur with FLT3-mutant clones and are enriched in crenolanib poor-responders. The remaining patients exhibit post-crenolanib expansion of mutations associated with epigenetic regulators, transcription factors, and cohesion factors, suggesting diverse genetic/epigenetic mechanisms of crenolanib resistance. Drug combinations in experimental models restore crenolanib sensitivity.

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    Additional processed data is available at vizome.org. Additional supplementary material accompanying the paper is available at http://vizome.org/additional_figures_BeatAML.html.

    Genotypes for 16 samples are not provided through the GDC due to failure to meet the GDC QC threshold for purity using the GATK 4.0 Mutect 2 pipeline. The published analyses were done with GATK 3.3. To be compliant with GDC SOPs, the samples are provided as BAM files only.

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