Abstract
Ponatinib is a multi-targeted third generation tyrosine kinase inhibitor (TKI) used in the treatment of chronic myeloid leukemia (CML) patients harboring the Abelson (Abl)-breakpoint cluster region (Bcr) T315I mutation. In spite of having superb clinical efficacy, ponatinib triggers severe vascular adverse events (VAEs) that significantly limit its therapeutic potential. On vascular endothelial cells (ECs), ponatinib promotes EC dysfunction and apoptosis, and inhibits angiogenesis. Furthermore, ponatinib-mediated anti-angiogenic effect has been suggested to play a partial role in systemic and pulmonary hypertension via inhibition of vascular endothelial growth factor receptor 2 (VEGFR2). Even though ponatinib-associated VAEs are well documented, their etiology remains largely unknown, making it difficult to efficiently counteract treatment-related adversities. Therefore, a better understanding of the mechanisms by which ponatinib mediates VAEs is critical. In cultured human aortic ECs (HAECs) treated with ponatinib, we found an increase in nuclear factor NF-kB/p65 phosphorylation and NF-kB activity, inflammatory gene expression, cell permeability, and cell apoptosis. Mechanistically, ponatinib abolished extracellular signal-regulated kinase 5 (ERK5) transcriptional activity even under activation by its upstream kinase mitogen-activated protein kinase kinase 5α (CA-MEK5α). Ponatinib also diminished expression of ERK5 responsive genes such as Krüppel-like Factor 2/4 (klf2/4) and eNOS. Because ERK5 SUMOylation counteracts its transcriptional activity, we examined the effect of ponatinib on ERK5 SUMOylation, and found that ERK5 SUMOylation is increased by ponatinib. We also found that ponatibib-mediated increased inflammatory gene expression and decreased anti-inflammatory gene expression were reversed when ERK5 SUMOylation was inhibited endogenously or exogenously. Overall, we propose a novel mechanism by which ponatinib up-regulates endothelial ERK5 SUMOylation and shifts ECs to an inflammatory phenotype, disrupting vascular homeostasis.
Highlights
chronic myeloid leukemia (CML) and Ph+ALL involve the reciprocal translocation of the Abl oncogene on chromosome 9 and the breakpoint cluster region (Bcr) on chromosome 22 [1,2,3]
In human aortic ECs (HAECs) treated with pharmacologically relevant concentrations of ponatinib (75 nM, 150 nM) [35, 65], we noted a significant increase on NF-kB p65 phosphorylation (Figure 1B) and NF-κB activity (Figure 1C)
We found that extracellular signal-regulated kinase 5 (ERK5) SUMOylation was significantly increased in both Human Umbilical Vein ECs (HUVECs) (Figure 3A,B) and HAECs (Figures 3C,D) treated with ponatinib, and that this increase was reversed in cells overexpressing deSUMOylation enzyme Sentrin/Small ubiquitin-like modifier (SUMO)-specific protease 2 (SENP2) (Figures 3C,D)
Summary
CML and Ph+ALL involve the reciprocal translocation of the Abl oncogene on chromosome 9 and the Bcr on chromosome 22 [1,2,3]. Diagnosed CML patients commonly receive imatinib (first generation TKI), a small molecule that binds the ATP pocket on the Bcr-Abl tyrosine kinase, as a first line of treatment [6, 7]. Because CML patients often develop Bcr-Abl point mutations conferring resistance to imatinib [8], dasatinib, and nilotinib (second generation TKIs) were generated [9]. Ponatinib (a third generation TKI) was designed to circumvent the sterical hindrance warranted by the T315I mutation [14,15,16,17] Since it is the only drug effective against this mutation, ponatinib has become the treatment of choice for CML patients harboring T315I Bcr-Abl [18,19,20,21,22,23]
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