Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers
Zoledronic acid enhances the efficacy of the MEK inhibitor trametinib in KRAS mutant cancers
复制标题
唑来膦酸增强 MEK 抑制剂曲美替尼 (Trametinib) 在 KRAS 突变癌症中的疗效
DOI：
10.1016/j.canlet.2018.10.022
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发表时间：
2019-02-01
期刊：
影响因子：
9.7
通讯作者：
Bi, Feng
中科院分区：
文献类型：
--
作者：
Dai, Xinyu;Xia, Hongwei;Bi, Feng
KRAS突变是人类癌症中最常见的突变类型。然而，直接药理抑制KRAS尚未在临床上取得成功。Trametinib （GSK1120212, Tram）是一种新的MEK抑制剂，通过抑制丝裂原活化蛋白激酶（MAPK）级联抑制RAS信号传导。与BRAF突变体肿瘤相比，Tram在KRAS突变体肿瘤中的临床应用效果有限。在这里，我们发现Tram治疗引起了上游RAS的反馈激活，从而在KRAS突变肿瘤中诱导磷酸化的MEK （pMEK）和磷酸化的ERK （pERK）反弹。这种持续ERK抑制的失败导致了耐药性。唑来膦酸（ZA）是一种含氮双膦酸盐，通过抑制RAS的异戊二烯化来破坏RAS的生物活性。令人惊讶的是，ZA克服了Tram耐药性，并且在KRAS突变肿瘤中体外和体内观察到增强的抗肿瘤活性。此外，ZA通过甲羟戊酸途径部分增强了Tram的作用。综上所述，两种fda批准的药物Tram和ZA的联合治疗可能代表了一种治疗KRAS突变型癌症的新治疗策略。
KRAS mutation is the most common type of mutation in human cancers. However, the direct pharmacological inhibition of KRAS has not been clinically successful. Trametinib (GSK1120212, Tram), a newer MEK inhibitor, inhibits RAS signaling through mitogen-activated protein kinase (MAPK) cascade suppression. The effectiveness of Tram in clinical practice is limited in KRAS mutant tumors compared to that in BRAF mutant tumors. Here, we found that Tram treatment provoked feedback activation of upstream RAS, thus causing an induction of phosphorylated MEK (pMEK) and phosphorylated ERK (pERK) rebound in KRAS mutant tumors. This failure of persistent ERK inhibition led to drug resistance. Zoledronic acid (ZA), a nitrogen-containing bisphosphonate, disrupts the biological activity of RAS by inhibiting its isoprenylation. Surprisingly, ZA overcame Tram resistance, and augmented antitumor activity was observed in KRAS mutant tumors both in vitro and in vivo. Furthermore, ZA enhanced the effect of Tram partially through the mevalonate pathway. In summary, the combination of the two FDA-approved drugs Tram and ZA may represent a novel therapeutic strategy for the treatment of KRAS mutant cancers.