2019
DOI: 10.1038/s41467-018-08263-x
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Clinical resistance to crenolanib in acute myeloid leukemia due to diverse molecular mechanisms

Abstract: 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 pat… Show more

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Cited by 128 publications
(145 citation statements)
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References 57 publications
(80 reference statements)
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“…It is notable, however, that in a study of clinical resistance to the type I inhibitor crenolanib, resistance-causing FLT3 TKD mutations were similarly identified in only a small proportion of patients. 32 This finding is congruent with results of our study and reinforces that type I inhibitors may be overall less susceptible to on-target resistance, as is suggested by prior mutagenesis studies which often identify less resistance mutations associated with type I inhibitors 17,33 than type II inhibitors 12,15,25,26 (supplemental Table 2) as well as by our recent report of non-FLT3 dependent gilteritinib resistance mechanisms. 37 The increased vulnerability of type II inhibitors to TKD mutations is likely attributable to the fact that type II inhibitors bind to allosteric sites in the inactive kinase conformation.…”
Section: Discussionsupporting
confidence: 92%
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“…It is notable, however, that in a study of clinical resistance to the type I inhibitor crenolanib, resistance-causing FLT3 TKD mutations were similarly identified in only a small proportion of patients. 32 This finding is congruent with results of our study and reinforces that type I inhibitors may be overall less susceptible to on-target resistance, as is suggested by prior mutagenesis studies which often identify less resistance mutations associated with type I inhibitors 17,33 than type II inhibitors 12,15,25,26 (supplemental Table 2) as well as by our recent report of non-FLT3 dependent gilteritinib resistance mechanisms. 37 The increased vulnerability of type II inhibitors to TKD mutations is likely attributable to the fact that type II inhibitors bind to allosteric sites in the inactive kinase conformation.…”
Section: Discussionsupporting
confidence: 92%
“…37,38 These results suggest that acquisition of new or parallel oncogenic driver mutations will be common, as has been reported with crenolanib. 32,37 Ultimately, although gilteritinib has activity against a wide variety of FLT3 mutations and appears less clinically vulnerable to on-target resistance, rational combination therapies will be required to suppress outgrowth of heterogeneous resistant leukemic clones.…”
Section: Discussionmentioning
confidence: 99%
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“…Characteristics of resistant clones after treatment with another type I inhibitor crenolanib were also different from those after type II inhibitors . In crenolanib‐treated patients, acquired mutations on the FLT3 gene were infrequent in residual AML cells after treatment.…”
Section: Secondary Resistance Mechanisms Of Flt3 Inhibitorsmentioning
confidence: 99%
“…For example, consider the epidermal growth factor receptors. The use of tyrosine kinase inhibitors (TKIs) as therapeutic agents for human myeloid leukemia has been shown to lead to resistance in patients due to a wide variety of off‐target mechanisms . After the treatment of sensitive or resistant chronic myeloid leukemia cell lines with three TKIs (imatinib, dasatinib, and nilotinib), whole transcriptome sequencing and SWATH‐based proteome analysis were used to discover off‐targets (CA1 and alpha‐synuclein) and biological pathways (oxidative stress responses, hypoxia conditions, and metabolic disruptions) related to TKI resistance .…”
Section: Summary and Future Directionsmentioning
confidence: 99%