AI Article Synopsis
- FLT3 mutations are common in AML and lead to a worse prognosis, but crenolanib, a powerful FLT3 inhibitor, shows effectiveness against certain mutations but leads to temporary responses before relapse.
- Research indicates that crenolanib doesn’t create secondary FLT3 mutations, but instead, leads to new mutations in NRAS and IDH2, along with other changes in genes related to epigenetics and transcription in resistant cases.
- Combining crenolanib with other drugs in tests may help overcome resistance and restore its effectiveness.
Article 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 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6335421 | PMC |
| http://dx.doi.org/10.1038/s41467-018-08263-x | DOI Listing |
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