Sprowl Jason A, Ong Su Sien, Gibson Alice A, Hu Shuiying, Du Guoqing, Lin Wenwei, Li Lie, Bharill Shashank, Ness Rachel A, Stecula Adrian, Offer Steven M, Diasio Robert B, Nies Anne T, Schwab Matthias, Cavaletti Guido, Schlatter Eberhard, Ciarimboli Giuliano, Schellens Jan H M, Isacoff Ehud Y, Sali Andrej, Chen Taosheng, Baker Sharyn D, Sparreboom Alex, Pabla Navjotsingh
Department of Pharmaceutical, Social and Administrative Sciences, School of Pharmacy, D'Youville College, Buffalo, New York 14201, USA.
Department of Chemical Biology &Therapeutics, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.
Nat Commun. 2016 Mar 16;7:10880. doi: 10.1038/ncomms10880.
Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters. We initially found that organic cation transporters (OCTs), uptake carriers of metformin and oxaliplatin, were inhibited by several clinically used TKIs. Mechanistic studies showed that these TKIs inhibit the Src family kinase Yes1, which was found to be essential for OCT2 tyrosine phosphorylation and function. Yes1 inhibition in vivo diminished OCT2 activity, significantly mitigating oxaliplatin-induced acute sensory neuropathy. Along with OCT2, other SLC-family drug transporters are potentially part of an extensive 'transporter-phosphoproteome' with unique susceptibility to TKIs. On the basis of these findings we propose that TKIs, an important and rapidly expanding class of therapeutics, can functionally modulate pharmacologically important proteins by inhibiting protein kinases essential for their post-translational regulation.
膜转运蛋白是治疗效果的关键决定因素。它们调节全身和细胞内的药物水平，影响疗效和毒性。在此，我们报告了药物转运蛋白与酪氨酸激酶抑制剂（TKIs）之间一种独特的磷酸化依赖性相互作用，这揭示了磷酸酪氨酸介导的对药物转运蛋白的广泛调控。我们最初发现，二甲双胍和奥沙利铂的摄取载体有机阳离子转运蛋白（OCTs）受到几种临床使用的TKIs的抑制。机制研究表明，这些TKIs抑制Src家族激酶Yes1，而Yes1被发现对OCT2酪氨酸磷酸化和功能至关重要。体内对Yes1的抑制降低了OCT2的活性，显著减轻了奥沙利铂诱导的急性感觉神经病变。与OCT2一样，其他SLC家族药物转运蛋白可能是广泛的“转运蛋白 - 磷酸蛋白质组”的一部分，对TKIs具有独特的敏感性。基于这些发现，我们提出，TKIs作为一类重要且迅速发展的治疗药物，可通过抑制对其翻译后调控至关重要的蛋白激酶，在功能上调节药理学上重要的蛋白质。
