Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib.
Cross-resistance to clinically used tyrosine kinase inhibitors sunitinib, sorafenib and pazopanib.
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DOI：
10.1007/s13402-015-0218-8
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发表时间：
2015-04
期刊：
影响因子：
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通讯作者：
Verheul HM
中科院分区：
文献类型：
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作者：
Gotink KJ;Rovithi M;de Haas RR;Honeywell RJ;Dekker H;Poel D;Azijli K;Peters GJ;Broxterman HJ;Verheul HM
当癌症治疗期间出现对酪氨酸激酶抑制剂（TKI）的耐药性时，切换到另一种TKI通常被认为是一种合理的选择。先前，我们报道了对舒尼替尼的耐药可能是由溶酶体隔离增加引起的，导致细胞内溶酶体储存增加，从而导致活性降低。在这里，我们研究了其他几种TKIs对（交叉）抗性发展的影响。癌细胞连续暴露于增加TKI浓度的环境3-4个月，可诱导TKI耐药性。（交叉）抗性用MTT细胞增殖试验评估。采用LC-MS/MS法测定细胞内TKI浓度。Western blotting检测溶酶体相关膜蛋白-1和- 2 （LAMP1/2）的表达。先前产生的舒尼替耐药（SUN）肾癌细胞（786-O）和结直肠癌细胞（HT-29）被发现对帕唑帕尼、厄洛替尼和拉帕替尼交叉耐药，但不耐索拉非尼。786-O和HT-29细胞暴露于索拉非尼、帕唑帕尼或厄洛替尼3-4个月诱导对帕唑帕尼和厄洛替尼耐药，但对索拉非尼不耐药。在帕唑帕尼和厄洛替尼中发现细胞内药物积累增加，但在暴露于索拉非尼的细胞中没有。通过LAMP1/2表达反映的溶酶体容量在耐药细胞中增加，而且是短暂的。未发现对mTOR抑制剂依维莫司的交叉耐药。我们的数据表明，肿瘤细胞可以对TKIs产生（交叉）耐药性，这种耐药性包括细胞内药物积累增加以及溶酶体储存增加。在几种TKI测试中发现了短暂（交叉）耐药，但依维莫司没有，这表明从TKI转向mTOR抑制剂可能是一种有吸引力的治疗选择。
When during cancer treatment resistance to a tyrosine kinase inhibitor (TKI) occurs, switching to another TKI is often considered as a reasonable option. Previously, we reported that resistance to sunitinib may be caused by increased lysosomal sequestration, leading to increased intracellular lysosomal storage and, thereby, inactivity. Here, we studied the effect of several other TKIs on the development of (cross-) resistance. TKI resistance was induced by continuous exposure of cancer cell lines to increasing TKI concentrations for 3–4 months. (Cross-) resistance was evaluated using MTT cell proliferation assays. Intracellular TKI concentrations were measured using LC-MS/MS. Western blotting was used to detect lysosome-associated membrane protein-1 and −2 (LAMP1/2) expression. The previously generated sunitinib-resistant (SUN) renal cancer cells (786-O) and colorectal cancer cells (HT-29) were found to be cross-resistant to pazopanib, erlotinib and lapatinib, but not sorafenib. Exposure of 786-O and HT-29 cells to sorafenib, pazopanib or erlotinib for 3–4 months induced drug resistance to pazopanib and erlotinib, but not sorafenib. Intracellular drug accumulation was found to be increased in pazopanib- and erlotinib-, but not in sorafenib-exposed cells. Lysosomal capacity, reflected by LAMP1/2 expression, was found to be increased in resistant cells and, in addition, to be transient. No cross-resistance to the mTOR inhibitor everolimus was detected. Our data indicate that tumor cells can develop (cross-) resistance to TKIs, and that such resistance includes increased intracellular drug accumulation accompanied by increased lysosomal storage. Transient (cross-) resistance was found to occur for several of the TKIs tested, but not for everolimus, indicating that switching from a TKI to a mTOR inhibitor may be an attractive therapeutic option.