Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling
Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling
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DOI：
10.1042/bst20110647
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发表时间：
2012-02-01
影响因子：
3.9
通讯作者：
Cook, Simon J.
中科院分区：
文献类型：
--
作者：
Little, Annette S.;Balmanno, Kathryn;Cook, Simon J.
Raf/MEK1/2[丝裂原活化蛋白激酶/ERK(细胞外信号调节蛋白)激酶1/2]/ERK1/2信号通路在人类肿瘤中由于BRAF或KRAS的突变而经常被激活。B-Raf和MEK1/2抑制剂目前正在接受临床评估，但它们的最终成功可能会受到获得性耐药性的限制。我们使用了B-Raf或K-Ras突变的结直肠癌细胞株来模拟对MEK1/2抑制剂selumetinib(AZD6244)的获得性耐药性。在细胞增殖实验中，塞鲁米替尼耐药细胞对其他MEK1/2抑制剂不敏感，在没有抑制剂的情况下，MEK1/2和ERK1/2活性以及细胞周期蛋白D1的丰度显著增加。这是由一个共同的机制驱动的，在该机制中，耐药细胞表现出各自驱动癌基因B-Raf(V600E)或K-Ras(G13D)的染色体内扩增。尽管从Raf到MEK1/2的信号通量增加，但在药物中维持的耐药细胞实际上表现出与亲本细胞相同的ERK1/2活性，这表明该途径被反馈控制重塑，以恢复维持这些细胞增殖所需的正常ERK1/2信号水平。这些结果为肿瘤细胞如何适应新的治疗方法提供了重要的新见解，并突出了自稳控制机制在Raf/MEK1/2/ERK1/2信号级联中的重要性。
The Raf/MEK1/2 [mitogen-activated protein kinase/ERK (extracellular-signal-regulated kinase) kinase 1/2]/ERK1/2 signalling pathway is frequently activated in human tumours due to mutations in BRAF or KRAS. B-Raf and MEK1/2 inhibitors are currently undergoing clinical evaluation, but their ultimate success is likely to be limited by acquired drug resistance. We have used colorectal cancer cell lines harbouring mutations in B-Raf or K-Ras to model acquired resistance to the MEK1/2 inhibitor selumetinib (AZD6244). Selumetinib-resistant cells were refractory to other MEK1/2 inhibitors in cell proliferation assays and exhibited a marked increase in MEK1/2 and ERK1/2 activity and cyclin D1 abundance when assessed in the absence of inhibitor. This was driven by a common mechanism in which resistant cells exhibited an intrachromosomal amplification of their respective driving oncogene, B-Raf(V600E) or K-Ras(G13D). Despite the increased signal flux from Raf to MEK1/2, resistant cells maintained in drug actually exhibited the same level of ERK1/2 activity as parental cells, indicating that the pathway is remodelled by feedback controls to reinstate the normal level of ERK1/2 signalling that is required and sufficient to maintain proliferation in these cells. These results provide important new insights into how tumour cells adapt to new therapeutics and highlight the importance of homoeostatic control mechanisms in the Raf/MEK1/2/ERK1/2 signalling cascade.