Patras de Campaigno Emilie, Bondon-Guitton Emmanuelle, Laurent Guy, Montastruc Francois, Montastruc Jean-Louis, Lapeyre-Mestre Maryse, Despas Fabien
Service de Pharmacologie Médicale et Clinique, CHU de Toulouse, 37 allées Jules Guesde, 31000, Toulouse, France.
UMR1027, Inserm, Université Paul Sabatier, Toulouse, France.
Br J Clin Pharmacol. 2017 Jul;83(7):1544-1555. doi: 10.1111/bcp.13238. Epub 2017 Feb 14.
The aims of the present study were to evaluate the risk of cardiac failure (CF) associated with 15 anticancer protein kinase inhibitors (PKIs) through a case/noncase analysis and to identify which PK(s) and pathways are involved in PKI-induced CF.
In order to evaluate the risk of CF, adjusted reporting odds ratios (aRORs) were calculated for the 15 anticancer PKIs in the World Health Organization safety report database (VigiBase®). We realised a literature review to identify 21 protein kinases (PKs) that were possibly involved in CF caused by PKIs. Pearson correlation coefficients (r) between aRORs and affinity data of the 15 PKIs for the 21 PKs were calculated to identify the cellular target most likely to be involved in PKI-induced CF.
A total of 141 601 individual case safety reports (ICSRs) were extracted from VigiBase® for the following PKIs: afatinib, axitinib, bosutinib, crizotinib, dasatinib, erlotinib, gefitinib, imatinib, lapatinib, nilotinib, pazopanib, ruxolitinib, sorafenib, sunitinib and vandetanib. Among them, 2594 ICSRs concerned CF. The disproportionality analysis revealed that, for dasatinib, imatinib, bosutinib, sunitinib and nilotinib, disproportionality for CF was significantly higher than for other PKIs, with aRORs of 2.52 [95% CI 2.26, 2.82], 1.79 (95% CI 1.57, 2.03), 1.73 (95% CI 1.18, 2.54), 1.67 (95% CI 1.51, 1.84) and 1.38 (95% CI 1.18, 1.61), respectively. Significant values for correlation coefficients between the product of dissociation constant (pKd) and aROR were observed for two non-receptor protein kinases: ABL1 (non-phosphorylated and phosphorylated forms) and ABL2 protein kinases, with values of r = 0.83 (P = 0.0001), r = 0.75 (P = 0.0014) and r = 0.78 (P = 0.0006), respectively.
We observed a higher disproportionality for CF with dasatinib, imatinib, bosutinib, sunitinib and nilotinib than with other PKIs. In addition, the study highlighted the role of ABL tyrosine kinases in CF caused by anticancer PKIs.
本研究旨在通过病例/非病例分析评估15种抗癌蛋白激酶抑制剂（PKIs）与心力衰竭（CF）相关的风险，并确定哪些蛋白激酶（PK）和信号通路参与PKI诱导的CF。
为评估CF风险，在世界卫生组织安全报告数据库（VigiBase®）中计算了15种抗癌PKIs的调整报告比值比（aRORs）。我们进行了文献综述，以确定可能参与PKIs导致的CF的21种蛋白激酶（PKs）。计算了15种PKIs对21种PKs的aRORs与亲和力数据之间的Pearson相关系数（r），以确定最可能参与PKI诱导的CF的细胞靶点。
从VigiBase®中提取了以下PKIs的总共141601份个体病例安全报告（ICSRs）：阿法替尼、阿昔替尼、博舒替尼、克唑替尼、达沙替尼、厄洛替尼、吉非替尼、伊马替尼、拉帕替尼、尼洛替尼、帕唑帕尼、鲁索替尼、索拉非尼、舒尼替尼和凡德他尼。其中，2594份ICSRs涉及CF。不成比例分析显示，对于达沙替尼、伊马替尼、博舒替尼、舒尼替尼和尼洛替尼，CF的不成比例性显著高于其他PKIs，aRORs分别为2.52 [95% CI 2.26, 2.82]、1.79（95% CI 1.57, 2.03）、1.73（95% CI 1.18, 2.54）、1.67（95% CI 1.51, 1.84）和1.38（95% CI 1.18, 1.61）。对于两种非受体蛋白激酶：ABL1（非磷酸化和磷酸化形式）和ABL2蛋白激酶，观察到解离常数（pKd）与aROR乘积之间的相关系数有显著值，r值分别为0.83（P = 0.0001）、0.75（P = 0.0014）和0.78（P = 0.0006）。
我们观察到达沙替尼、伊马替尼、博舒替尼、舒尼替尼和尼洛替尼导致CF的不成比例性高于其他PKIs。此外，该研究突出了ABL酪氨酸激酶在抗癌PKIs引起的CF中的作用。
