Despite the use of several modern, high-throughput analytical methods, researchers from Russia were unable to find any reliable molecular markers to help predict which patients with Philadelphia chromosome-positive chronic myeloid leukemia (CML) might respond best to treatment with a tyrosine kinase inhibitor (TKI), according to a recent study.1
As many as 1 in 5 patients with CML will have primary resistance or intolerance to one of the most common TKIs, imatinib, but instruments to help predict which patients will become resistant are lacking.
“To date, researchers performed several attempts to detect genetic markers associated with resistance to TKI or nonoptimal response to targeted therapy,” wrote study researcher Alexander V. Lavrov, of the Research Centre for Medical Genetics, Moscow, Russia. “It was shown that the resistance of leukemic cells is associated with the enhanced PI3K/AKT, RAF/MEK/ERK and STAT3 signaling pathways. At the same time, studies involving patients with different responses to TKI, show influence of genetic polymorphisms in TKI metabolizers’ genes, BIM gene, FAS gene, DNMT3A, and ASXL1 genes.”
In addition, previous research has shown that expression profiles between optimal responders and nonoptimal responders also vary greatly; however, most of these studies were conducted prior to the next-generation sequencing era.
In the current study, Lavrov and colleagues sought to identify new molecular markers of TKI therapy efficacy in patients with CML using whole-exome sequencing. To do that, they analyzed patients with newly diagnosed Ph+ CML using genotyping of selected polymorphisms in blood samples from 62 patients, expression profiling of 33 RNA samples, and miRNA profiling of 800 miRNA in 12 blood samples.
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