Pharmacologic inhibition of mTOR antagonizes the cytotoxic activity of pemetrexed in non-small cell lung cancer
Pharmacologic inhibition of mTOR antagonizes the cytotoxic activity of pemetrexed in non-small cell lung cancer
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DOI：
10.1007/s00432-011-1123-9
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发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Breitenbuecher, Frank
中科院分区：
文献类型：
--
作者：
Markova, Boyka;Haehnel, Patricia S.;Breitenbuecher, Frank
培美曲塞是胸苷酸合成酶 (TS) 和其他叶酸依赖性酶的抑制剂，在临床上对患有“非鳞状”非小细胞肺癌 (NSCLC) 的患者有效。 TS 的高表达被认为是预测培美曲塞耐药性的生物标志物。在此背景下，我们研究了抑制mTOR是否可以降低TS的表达，从而使NSCLC细胞对培美曲塞敏感。使用鳞状细胞癌和腺癌NSCLC细胞系，我们观察到组成型TS表达水平与培美曲塞体外对生长抑制或细胞凋亡的敏感性不相关。有趣的是，培美曲塞在所有细胞系中强烈诱导 TS RNA 和蛋白质表达。变构“rapalogue”mTOR 抑制剂依维莫司抑制组成型 TS 表达，但不抑制培美曲塞诱导的 TS 表达。令人惊讶的是，与依维莫司联合治疗可保护 NSCLC 细胞免受培美曲塞诱导的细胞凋亡。与单独培美曲塞相比，这导致培美曲塞加依维莫司治疗的 NSCLC 细胞的长期克隆存活率增加。当依维莫司与重组 TRAIL（一种不依赖于增殖的促凋亡剂）联合使用时，没有观察到这种负面相互作用。Rapalogues 可能通过减慢细胞周期进程来抑制培美曲塞的抗肿瘤活性。在 NSCLC 治疗中联合培美曲塞和 mTOR 抑制剂时应考虑这一点。
Pemetrexed, an inhibitor of thymidylate synthase (TS) and additional folate-dependent enzymes, is clinically active in patients suffering from "non-squamous" non-small cell lung cancer (NSCLC). High expression of TS has been implied as biomarker predictive of resistance to pemetrexed. Against this background, we studied whether inhibition of mTOR could lower expression of TS and thus sensitize NSCLC cells to pemetrexed.Using squamous cell carcinoma and adenocarcinoma NSCLC cell lines, we observed that constitutive TS expression levels failed to correlate with sensitivity to growth inhibition or apoptosis imposed by pemetrexed in vitro. Interestingly, pemetrexed strongly induced TS RNA and protein expression in all cell lines. The allosteric "rapalogue" mTOR inhibitor everolimus suppressed constitutive, but not pemetrexed-induced TS expression. Surprisingly, cotreatment with everolimus protected NSCLC cells against pemetrexed-induced apoptosis. This resulted in increased long-term clonogenic survival of NSCLC cells treated with pemetrexed plus everolimus as compared to pemetrexed alone. No such negative interaction was observed when everolimus was combined with recombinant TRAIL, a proliferation-independent proapoptotic agent.Rapalogues may suppress the antitumor activity of pemetrexed by slowing cell cycle progression. This should be considered when combining pemetrexed and mTOR inhibitors in NSCLC treatment.