Global target profile of the kinase inhibitor bosutinib in primary chronic myeloid leukemia cells

Abstract

The detailed molecular mechanism of action of secondgeneration BCR-ABL tyrosine kinase inhibitors, including perturbed targets and pathways, should contribute to rationalized therapy in chronic myeloid leukemia (CML) or in other affected diseases. Here, we characterized the target profile of the dual SRC/ABL inhibitor bosutinib employing a two-tiered approach using chemical proteomics to identify natural binders in whole cell lysates of primary CML and K562 cells in parallel to in vitro kinase assays against a large recombinant kinase panel. The combined strategy resulted in a global survey of bosutinib targets comprised of over 45 novel tyrosine and serine/ threonine kinases. We have found clear differences in the target patterns of bosutinib in primary CML cells versus the K562 cell line. A comparison of bosutinib with dasatinib across the whole kinase panel revealed overlapping, but distinct, inhibition profiles. Common among those were the SRC, ABL and TEC family kinases. Bosutinib did not inhibit KIT or platelet-derived growth factor receptor, but prominently targeted the apoptosis-linked STE20 kinases. Although in vivo bosutinib is inactive against ABL T315I, we found this clinically important mutant to be enzymatically inhibited in the midnanomolar range. Finally, bosutinib is the first kinase inhibitor shown to target CAMK2G, recently implicated in myeloid leukemia cell proliferation.

Identification of Kinase Inhibitor Targets in the Lung Cancer Microenvironment by Chemical and Phosphoproteomics

“…It is important to note that for the targets that are also covered by in vitro profiling panels, we observed good consistency between data from the different technologies, which cross-validates the approaches (Table S9). (23, 44, 46) In addition, chemical proteomics showed that dasatinib and sunitinib engage several protein complexes through their kinase targets, some of which have been described to play important roles in lung cancer. For instance, sunitinib specifically interacted with TBK1, IKBKE and AMPK complexes.…”

Tyrosine kinase inhibitor associated vascular toxicity in chronic myeloid leukemia

“…Targeting of NQO2 by imatinib and nilotinib may lead to unwanted drug-drug interactions. PDGF-R and C-kit could potentially provide explanations for the vascular toxicity since they both effect the regulation of vascular and perivascular cells [13], however they are targeted by many of the TKIs, possibly excluding bosutinib [44].…”

Chronic myeloid leukemia: reminiscences and dreams

“…123 Phase II studies of once daily bosutinib 500 mg/day in CML patients who were either resistant or intolerant to imatinib demonstrated a CCyR of 47%, an overall survival at two years of 88% in the imatinib-resistant cohort, and a remarkable 98% in the imatinib intolerant cohort; three years later, 40% of patients remained on bosutinib. [124][125][126][127] The principal side-effects included diarrhea, abnormal liver chemistry and various skin rashes, all of which were easily manageable with dose reduction and/or concomitant medications (Table 2).…”