Multiomic Profiling of Tyrosine Kinase Inhibitor-Resistant K562 Cells Suggests Metabolic Reprogramming To Promote Cell Survival

Resistance to chemotherapy can occur
through a wide variety of
mechanisms. Resistance to tyrosine kinase inhibitors (TKIs) often
arises from kinase mutationshowever, “off-target”
resistance occurs but is poorly understood. Previously, we established
cell line resistance models for three TKIs used in chronic myeloid
leukemia treatment, and found that resistance was not attributed entirely
to failure of kinase inhibition. Here, we performed global, integrated
proteomic and transcriptomic profiling of these cell lines to describe
mechanisms of resistance at the protein and gene expression level.
We used whole transcriptome sequencing and SWATH-based data-independent
acquisition mass spectrometry (DIA-MS), which does not require isotopic
labels and provides quantitative measurements of proteins in a comprehensive,
unbiased fashion. The proteomic and transcriptional data were correlated
to generate an integrated understanding of the gene expression and
protein alterations associated with TKI resistance. We defined mechanisms
of resistance and two novel markers, CA1 and alpha-synuclein, that
were common to all TKIs tested. Resistance to all of the TKIs was
associated with oxidative stress responses, hypoxia signatures, and
apparent metabolic reprogramming of the cells. Metabolite profiling
and glucose-dependence experiments showed that resistant cells had
routed their metabolism through glycolysis (particularly through the
pentose phosphate pathway) and exhibited disruptions in mitochondrial
metabolism. These experiments are the first to report a global, integrated
proteomic, transcriptomic, and metabolic analysis of TKI resistance.
These data suggest that although the mechanisms are complex, targeting
metabolic pathways along with TKI treatment may overcome pan-TKI resistance.